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Background: Human interleukin-22 (IL-22) is known as a "dual function" cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis. Methods: We used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis. Results: We demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A. Conclusions: We developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development. [ABSTRACT FROM AUTHOR]

Background: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear. Methods: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels). Results: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2. Conclusion: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management. [ABSTRACT FROM AUTHOR]

Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP. Highlights: 1. Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. 2. IL-22 is a potential indicator for monitoring organ dysfunction and severity of severe acute pancreatitis (SAP). 3. IL-22 acts as a protective factor against acinar cell damage by suppressing autophagy and reducing the infiltration of inflammatory cells. 4. IL-22 alleviate SAP-induced multiorgan injury. 5. IL-22 protect SAP-induced intestinal barrier damage. [ABSTRACT FROM AUTHOR]

Background: Many neurodevelopmental abnormalities are connected to autism spectrum disorder (ASD), which can result in inflammation and elevated cytokine levels due to immune system dysregulation. Interleukin (IL)-17 A and IL-22 have been linked to the regulation of host defense against pathogens at the barrier surface, the regeneration of injured tissue, and the integration of the neurological, endocrine, and immune systems. Several studies have investigated the possible connection between IL-17 A and ASD as well as the severity of behavioral symptoms, but few of them included IL-22. Objectives: To measure serum levels of interleukin (IL)-17 A and IL-22 in children with ASD and to investigate their association with disease severity. Methods: This pilot study was performed on 24 children with ASD and 24 matched controls. Childhood Autism Rating Scale (CARS) assessed ASD severity, and serum levels of IL-17 A and IL-22 were assessed by enzyme-linked immunosorbent assay (ELISA). Results: In ASD patients, serum levels of IL-17 A and IL-22 showed a significant increase compared to controls (p-values < 0.001). We compared serum levels of IL-17 A and IL-22 according to the severity categories by CARS and could not find any significant differences (p-values > 0.05). Only IL-22 had a significant positive correlation with ASD severity by CARS scores. Conclusions: Raised serum levels of IL-17 A and IL-22 are associated with ASD; only IL-22, not IL-17 A, is correlated with ASD severity. This finding proposes IL-22 as a possible future effective target for ASD treatment. To fully comprehend the significance of these cytokines in ASD and their possible effects on ASD diagnosis and treatment, more research on a wider scale is required. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is known as a prevalent but complicated gynecologic disease throughout the reproductive period. Typically, it is characterized by phenotypic manifestations of hyperandrogenism, polycystic ovary morphology, and persistent anovulation. For now, the therapeutic modality of PCOS is still a formidable challenge. Metabolic aberrations and immune challenge of chronic low-grade inflammatory state are significant in PCOS individuals. Recently, interleukin-22 (IL-22) has been shown to be therapeutically effective in immunological dysfunction and metabolic diseases, which suggests a role in the treatment of PCOS. In this review, we outline the potential mechanisms and limitations of IL-22 therapy in PCOS-related metabolic disorders including its regulation of insulin resistance, gut barrier, systemic inflammation, and hepatic steatosis to generate insights into developing novel strategies in clinical practice. [ABSTRACT FROM AUTHOR]

The innate immune system provides a defense against invading pathogens by inducing various interferon (IFN)-stimulated genes (ISGs). We recently reported that tripartite motif protein 25 (TRIM25), an important ISG, was highly upregulated in duck embryo hepatocyte cells (DEFs) after infection with duck viral hepatitis A virus type 1 (DHAV-1). However, the mechanism of upregulation of TRIM25 remains unknown. Here we reported that interleukin-22 (IL-22), whose expression was highly facilitated in DEFs and various organs of 1-day-old ducklings after DHAV-1 infection, highly enhanced the IFN-λ-induced production of TRIM25. The treatment with IL-22 neutralizing antibody or the overexpression of IL-22 highly suppressed or facilitated TRIM25 expression, respectively. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) was crucial for the process of IL-22 enhancing IFN-λ-induced TRIM25 production, which was suppressed by WP1066, a novel inhibitor of STAT3 phosphorylation. The overexpression of TRIM25 in DEFs resulted in a high production of IFNs and reduced DHAV-1 replication, whereas the attenuated expression of IFNs and facilitated replication of DHAV-1 were observed in the RNAi group, implying that TRIM25 defended the organism against DHAV-1 propagation by inducing the production of IFNs. In summary, we reported that IL-22 activated the phosphorylation of STAT3 to enhance the IFN-λ-mediated TRIM25 expression and provide a defense against DHAV-1 by inducing IFN production. [ABSTRACT FROM AUTHOR]

Background: Excessive inflammatory response is the primary cause of early death in patients with endotoxemia. Interleukin 22 (IL-22) has been shown to play critical roles in the modulation of infectious diseases, but its function in regulating immune responses during endotoxemia remains unclear. Methods: Lipopolysaccharide (LPS) was used to induce endotoxemia mouse model with or without a recombinant fusion protein containing human IL-22 (F-652). IL-6, TNF-α, IL-1β, and MCP-1 were measured by ELISA assays. The type of macrophage was assessed by flow cytometry. Real-time PCR was used to detect the expression of S100A9. Results: We found that F-652 injection significantly improved the survival rates and reduced pro-inflammatory cytokines (IL-6, TNF-a, IL-1β, MCP-1) in LPS-induced endotoxemia mice. However, the mice injected with F-652 had a higher number of infiltrated immune cells after LPS treatment, suggesting an impaired immune response. Flow cytometry analysis showed a higher number of F4/80+Ly6GhiLy6Chi cells that highly expressed M2-like macrophage markers (Ym1, Arg, CCL17) in the peritoneal cavity of the F-652-treated endotoxemia mice. Further investigation found that these suppressive M2 macrophages might be induced by F-652 since the F-652 treatment could increase S100A9 in vitro. Conclusions: Our study suggests that IL-22 has a protective role against endotoxemia by inducing the development of immunosuppressive cells through S100A9. [ABSTRACT FROM AUTHOR]

Background: There is substantial evidence indicating that cytokines play a role in the immune defense against tuberculosis. This study aims to evaluate the levels of various cytokines in pleural effusion to ditinguish between tuberculosis pleurisy and malignant pleurisy., Methods: A total of 82 participants with pleural effusion were included in the training cohort, and 76 participants were included in the validation cohort. The individuals were divided into tuberculosis and malignant pleurisy groups. The concentrations of interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, interferon-γ (IFN-γ), soluble CD40 ligand (sCD40L) and tumor necrosis factor-α (TNF-α) in pleural effusion were measured using a multiplex cytokine assay. The threshold values were calculated according to the receiver operating characteristic (ROC) curve analysis to aid in diagnosing tuberculosis pleurisy. Furthermore, the combined measure was validated in the validation cohort., Results: The levels of all 14 cytokines in pleural effusion were significantly higher in participants with tuberculosis compared to those with malignant pleurisy (all P < 0.05). The area under the curve (AUC) was ≥ 0.920 for the IL-22, sCD40L, IFN-γ, TNF-α and IL-31, which were significantly increased in tuberculous pleural effusion (TPE) compared to MPE in the training cohort. Threshold values of 95.80 pg/mL for IFN-γ, 41.80 pg/mL for IL-31, and 18.87 pg/mL for IL-22 provided ≥ 90% sensitivity and specificity in distinguishing between tuberculosis pleurisy and malignant pleurisy in the training cohort. Among these, IL-22 combined with sCD40L showed the best sensitivity and specificity (94.0% and 96.9%) for diagnosing tuberculosis pleurisy, and this finding was validated in the validation cohort., Conclusion: We demonstrated that the levels of IL-1β, IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in pleural effusion had significant difference between tuberculosis pleurisy and malignant pleurisy. Specifically, IL-22 ≥ 18.87 pg/mL and sCD40L ≥ 53.08 pg/mL can be clinically utilized as an efficient diagnostic strategy for distinguishing tuberculosis pleurisy from malignant pleurisy., (© 2024. The Author(s).)

Background: Allergic asthma is a chronic airway inflammatory disease with a number of cytokines participating in its pathogenesis and progress. Interleukin (IL)-22, which is derived from lymphocytes, acts on epithelial cells and play a role in the chronic airway inflammation. However, the actual role of IL-22 in allergic asthma is still unclear. Therefore, we explored the effect of IL-22 on allergic airway inflammation and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-induced asthma mouse model.Methods: To evaluate the effect of IL-22 in an allergic asthma model, BALB/c mice were sensitized and challenged with OVA; then the recombinant mouse IL-22 was administered intranasally 24 h prior to each challenge. The IL-22 levels in lung homogenates and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay, respectively. AHR was evaluated through indicators including airways resistance (Rrs), elastance (Ers) and compliance (Crs); the inflammatory cell infiltration was assessed by quantification of differential cells counts in BALF and lung tissues stained by hematoxylin and eosin (H&E); IL-22 specific receptors were determined by immunohistochemistry staining.Results: The concentration of IL-22 was significantly elevated in the OVA-induced mice compared with the control mice in lung homogenates and BALF. In the OVA-induced mouse model, IL-22 administration could significantly attenuate AHR, including Rrs, Ers and Crs, decrease the proportion of eosinophils in BALF and reduce inflammatory cell infiltration around bronchi and their concomitant vessels, compared with the OVA-induced group. In addition, the expression of IL-22RA1 and IL-10RB in the lung tissues of OVA-induced mice was significantly increased compared with the control mice, while it was dramatically decreased after the treatment with IL-22, but not completely attenuated in the IL-22-treated mice when compared with the control mice.Conclusion: Interleukin-22 could play a protective role in an OVA-induced asthma model, by suppressing the inflammatory cell infiltration around bronchi and their concomitant vessels and airway hyperresponsiveness, which might associate with the expression of its heterodimer receptors. Thus, IL-22 administration might be an effective strategy to attenuate allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis is recognized as a chronic immuno-inflammatory disease that is characterized by the accumulation of immune cells and lipids in the vascular wall. In this review, we focus on the latest advance regarding the regulation and signaling pathways of IL-22 and highlight its impacts on atherosclerosis. Main body: IL-22, an important member of the IL-10 family of cytokines, is released by cells of the adaptive and innate immune system and plays a key role in the development of inflammatory diseases. The binding of IL-22 to its receptor complex can trigger a diverse array of downstream signaling pathways, in particular the JAK/STAT, to induce the expression of chemokines and proinflammatory cytokines. Recently, numerous studies suggest that IL-22 is involved in the pathogenesis of atherosclerosis by regulation of VSMC proliferation and migration, angiogenesis, inflammatory response, hypertension, and cholesterol metabolism. Conclusion: IL-22 promotes the development of atherosclerosis by multiple mechanisms, which may be a promising therapeutic target in the pathogenesis of atherosclerosis. [ABSTRACT FROM AUTHOR]

Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is produced by a number of immune cells involved in the immune microenvironment of the body. IL-22 plays its pivotal roles by binding to the IL-22 receptor complex (IL-22R) and subsequently activating the IL-22R downstream signalling pathway. It has recently been reported that IL-22 also contributes to the pathogenesis of many connective tissue diseases (CTDs). In this review, we will discuss the role of IL-22 in several CTDs, such as system lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis and dermatomyositis, suggesting that IL-22 may be a potential therapeutic target in CTDs. [ABSTRACT FROM AUTHOR]

Background: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown., Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype., Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract., (© 2024. The Author(s).)

Background: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. Methods: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. Results: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. Conclusion: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy. Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1 [ABSTRACT FROM AUTHOR]

Background: Interleukin-22 (IL-22) belongs to the IL-10 cytokine family and is mainly produced by activated Th1 cells. Although IL-22 expression is reported to be elevated in many cancers, and increased IL-22 expression correlates with tumor progression and poor prognosis, little is known about the role of IL-22 in papillary thyroid cancer (PTC). We previously demonstrated that IL-22 promotes PTC cell migration and invasion through the microRNA-595/Sox17 axis. Methods: We used qRT-PCR and western blot to determine TRIM30, Sox17 and β-catenin expression in PTC cells. Knockdown and overexpression were performed to detect the role of TRIM30/Sox17/β-catenin axis on the migration and invasion PTC cells. Co-IP were used to determine the interaction between TRIM30 and Sox17. Findings: In this study, we demonstrated that IL-22 triggered tripartite-motif protein 30 (TRIM30) association with Sox17, thereby mediating K48-linked polyubiquitination of Sox17. We then demonstrated that TRIM30 was a positive regulator of IL-22-regulated migration and invasion of PTC cells. We also found that IL-22 induced the transcriptional activity of β-catenin and translocation of β-catenin from cytosol to the nucleus. Upon investigating the mechanisms behind this event, we found that IL-22 disrupted Sox17/β-catenin interactions by inducing TRIM30/Sox17 interactions, leading to promotion of β-catenin-dependent signaling. The analysis of hundreds of clinical specimens revealed that IL-22, TRIM30 and β-catenin levels were upregulated in PTC tissues compared with normal thyroid, and that their expression levels were closely correlated. Taken together, under the influence of IL-22, by sequestration of Sox17, TRIM30 promotes β-catenin-dependent signaling that promotes PTC cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Cytokines play a crucial role in regulating the function of the immune system by controlling the production, differentiation, and activity of immune cells. Occult hepatitis C virus (OHCV) infection can lead to liver damage, including cirrhosis and hepatocellular carcinoma. This study investigates the immunopathogenic impact of the cytokines IL-17 and IL-22 in OHCV infection compared to chronic hepatitis C (CHC) infection., Methods: We studied three groups of patients: 35 with OHCV, 100 untreated patients with CHC, and 30 healthy control subjects. All subjects underwent physical examination and biochemical testing. We used the sandwich enzyme-linked immunosorbent assay method to measure serum IL-17 and IL-22 levels in all groups., Results: Compared to the occult and control groups, the CHC group had significantly higher serum IL-17 levels (p < 0.001). The occult group also had higher serum IL-17 levels compared to the control group (p < 0.0001). There were no significant differences in IL-22 levels across the research groups. In the OHCV group, individuals with moderate inflammation (A2-A3) had significantly higher serum IL-17 levels than those with minimal inflammation (A0-A1), while in the CHC group, this difference was not statistically significant (p = 0.601). Neither the occult nor the CHC groups showed a correlation between serum IL-22 and inflammatory activity. There was no significant correlation between the levels of IL-17 or IL-22 and the stage of fibrosis/cirrhosis in either group. ROC curves were calculated for serum IL-17 and IL-22 levels and occult HCV infection, with cut-off values set at ≤ 32.1 pg/ml and < 14.3 pg/ml for IL-17 and IL-22, respectively. The AUROC (95%CI) was significantly higher for IL-17 than IL-22 (0.829 (0.732-0.902) vs. 0.504 (0.393-0.614), p < 0.001), suggesting that IL-17 has a stronger correlation with infection risk than IL-22., Conclusion: This study suggests that IL-17 may be involved in the immunopathogenesis of OHCV infection, especially in patients with moderate inflammation., (© 2024. The Author(s).)

Background: Interleukin-22 (IL-22) plays a prominent role in epithelial regeneration and dampening of chronic inflammatory responses by protecting intestinal stem cells from immune-mediated tissue damage. IL-22 has a considerable therapeutic potential in graft-versus-host disease (GVHD), which is a frequent and challenging complication following allogeneic stem cell transplantation. The aim of our study was to engineer Lactobacillus for delivery of IL-22 directly to the intestinal mucosa as a new therapeutic strategy for GVHD. Results: The secretion and surface anchoring of mouse IL-22 by Lactobacillus paracasei BL23 was demonstrated by Western blot and flow cytometry. Both secreted and anchored mouse IL-22 produced by Lactobacillus was biologically active, as determined by its ability to induce IL-10 secretion in the Colo 205 human colon cancer cell line. Conclusions: We have demonstrated the secretion and surface anchoring of bioactive IL-22 by Lactobacillus. Our results suggest that IL-22 expressing lactobacilli may potentially be a useful mucosal therapeutic agent for the treatment of GVHD, provided that chromosomal integration of the IL-22 expression cassettes can be achieved. [ABSTRACT FROM AUTHOR]

Aims: Interleukin-22 (IL-22) has beneficial effects on body weight, insulin resistance and inflammation in different mouse models, but its relevance for the development of type 2 diabetes in humans is unknown. We aimed to identify correlates of serum IL-22 levels and to test the hypothesis that higher IL-22 levels are associated with lower diabetes incidence. Methods: Cross-sectional associations between serum IL-22, cardiometabolic risk factors and glucose tolerance status were investigated in 1107 persons of the population-based KORA F4 study. The prospective association between serum IL-22 and incident type 2 diabetes was assessed in 504 initially non-diabetic study participants in both the KORA F4 study and its 7-year follow-up examination KORA FF4, 76 of whom developed diabetes. Results: Male sex, current smoking, lower HDL cholesterol, lower estimated glomerular filtration rate and higher serum interleukin-1 receptor antagonist were associated with higher IL-22 levels after adjustment for confounders (all P < 0.05). Serum IL-22 showed no associations with glucose tolerance status, prediabetes or type 2 diabetes. Baseline serum IL-22 levels (median, 25th/75th percentiles) for incident type 2 diabetes cases and non-cases were 6.28 (1.95; 12.35) and 6.45 (1.95; 11.80) pg/ml, respectively (age and sex-adjusted P = 0.744). The age and sex-adjusted OR (95% CI) per doubling of IL-22 for incident type 2 diabetes of 1.02 (0.85; 1.23) was almost unchanged after consideration of further confounders. Conclusions: High serum levels of IL-22 were positively rather than inversely associated with several cardiometabolic risk factors. However, these associations did not translate into an increased risk for type 2 diabetes. Thus, our data argue against the utility of IL-22 as biomarker for prevalent or incident type 2 diabetes in humans, but identify potential determinants of IL-22 levels which merits further research in the context of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: The immunity of CD4 + T cell subsets against human cytomegalovirus (HCMV) is considerable due to their essential role in controlling the infection in transplant individuals. Previously explained CD4 + subsets such as T helper (Th) 1 have been proven to have a protective role against HCMV infection, while the role of the recently identified Th22 subset has not been described yet. Here, the frequency changes of Th22 cells and the IL-22 cytokine production were investigated in kidney transplant recipients with and without HCMV infection., Methods: Twenty kidney transplant patients and ten healthy controls were enrolled in this study. Patients were categorized into HCMV + and HCMV- groups based on the HCMV DNA real-time PCR results. After isolating CD4 + T cells from PBMCs, the phenotype (CCR6 + CCR4 + CCR10 + ) and cytokine profile (IFN-γ - IL-17 - IL-22 + ) of Th22 cells were analyzed by flow cytometry. The gene expression of Aryl Hydrocarbon Receptor (AHR) transcription factor was analyzed by real-time PCR., Results: The phenotype frequency of these cells was lower in recipients with infection than in those without infection and healthy controls (1.88 ± 0.51 vs. 4.31 ± 1.05; P = 0.03 and 4.22 ± 0.72; P = 0.01, respectively). A lower Th22 cytokine profile was observed in patients with infection than in the two other groups (0.18 ± 0.03 vs. 0.20 ± 0.03; P = 0.96 and 0.33 ± 0.05; P = 0.04, respectively). AHR expression was also lower in patients with active infection., Conclusions: Overall, this study for the first time suggests that the reduced levels of Th22 subset and IL-22 cytokine in patients with active HCMV infection might indicate the protective role of these cells against HCMV., (© 2023. The Author(s).)

Background: IL-22 is induced by aryl hydrocarbon receptor (AhR) signaling and plays a critical role in gastrointestinal barrier function through effects on antimicrobial protein production, mucus secretion, and epithelial cell differentiation and proliferation, giving it the potential to modulate the microbiome through these direct and indirect effects. Furthermore, the microbiome can in turn influence IL-22 production through the synthesis of L-tryptophan (L-Trp)-derived AhR ligands, creating the prospect of a host-microbiome feedback loop. We evaluated the impact IL-22 may have on the gut microbiome and its ability to activate host AhR signaling by observing changes in gut microbiome composition, function, and AhR ligand production following exogenous IL-22 treatment in both mice and humans., Results: Microbiome alterations were observed across the gastrointestinal tract of IL-22-treated mice, accompanied by an increased microbial functional capacity for L-Trp metabolism. Bacterially derived indole derivatives were increased in stool from IL-22-treated mice and correlated with increased fecal AhR activity. In humans, reduced fecal concentrations of indole derivatives in ulcerative colitis (UC) patients compared to healthy volunteers were accompanied by a trend towards reduced fecal AhR activity. Following exogenous IL-22 treatment in UC patients, both fecal AhR activity and concentrations of indole derivatives increased over time compared to placebo-treated UC patients., Conclusions: Overall, our findings indicate IL-22 shapes gut microbiome composition and function, which leads to increased AhR signaling and suggests exogenous IL-22 modulation of the microbiome may have functional significance in a disease setting. Video Abstract., (© 2023. The Author(s).)

Background: Interleukin-22 (IL-22) is involved in lung diseases such as pneumonia, asthma and lung cancer. Lavage mirrors the local environment, and may provide insights into the presence and role of IL-22 in patients.Methods: Bronchoscopic lavage (BL) samples (n = 195, including bronchoalveolar lavage and bronchial washings) were analysed for IL-22 using an enzyme-linked immunosorbent assay. Clinical characteristics and parameters from lavage and serum were correlated with lavage IL-22 concentrations.Results: IL-22 was higher in lavage from patients with lung disease than in controls (38.0 vs 15.3 pg/ml, p < 0.001). Patients with pneumonia and lung cancer had the highest concentrations (48.9 and 33.0 pg/ml, p = 0.009 and p < 0.001, respectively). IL-22 concentration did not correlate with systemic inflammation. IL-22 concentrations did not relate to any of the analysed cell types in BL indicating a potential mixed contribution of different cell populations to IL-22 production.Conclusions: Lavage IL-22 concentrations are high in patients with lung cancer but do not correlate with systemic inflammation, thus suggesting that lavage IL-22 may be related to the underlying malignancy. Our results suggest that lavage may represent a distinct compartment where the role of IL-22 in thoracic malignancies can be studied. [ABSTRACT FROM AUTHOR]

Background: Children are prone to get infections, especially in the respiratory system and the gut mainly because their immune system is immature. T cells significantly contribute to the prevention of infections, and different helper T cell (Th) subsets play different anti-pathogen roles. Interleukin (IL)-22 producing by T-helper 22 cells (Th22) play an important role in host defense against Gram-negative bacterial organisms in gut and lung. T-helper 17 cells (Th17) protect against extracelluar bacteria and fungi especially at the epithelial surface. However, there is no report comparing IL-22 producing T cells and Th17 cells in healthy young children to adults. Methods: Flow cytometry (FCM) was used to observe whether Th22 subset existed in the peripheral blood of healthy young children. Meanwhile, we determined the frequencies of Th subsets including Th17, Th1 and Th2, cytotoxic T (Tc) 1 subset, CD4+ and CD8+ memory T cells in the peripheral blood of both young children and adults. Results: In the present study, we demonstrated that Th22 subset existed in peripheral blood of children, with IL-22 mainly secreted by CD4 + CD45RO+ memory T cells. Moreover, we observed that IL-22 + CD4 + T cells and Th subsets including Th17, Th1, and Th2 frequencies of young children (1-6 years old) were significantly lower than adults. While the Th1 frequency from Group A (1-3 years old) was markedly lower than that from Group B (4-6 years old). No significant differences of Th17 or IL-22 + CD4 + T cells frequencies were observed between these two groups. In addition, Tc1 subset frequencies were also remarkably lower in young children than in adults. Furthermore, lower frequencies of CD45RO+ memory CD4+ and CD8+ T cells in young children than in adults, and significant correlation between CD45RO+ memory CD4 + T cells and IL-22 + CD4 + T cells, Th1, Th17 were observed. Conclusions: Th22 subset exists in the peripheral blood of young children. Compared with adults, there are lower frequencies of IL-22 + CD4 + T cells, as well as Th1, Th17, Th2 and Tc1 subsets in the peripheral blood of young children. [ABSTRACT FROM AUTHOR]

Inflammatory processes and metabolic alterations are supposed to substantially interact. Recently, cumulating reports describe a profound role of interleukin(IL)-22 in this relationship. IL-22 is a particular kind of immune mediator that is produced by certain lymphocyte populations and regulates the function of several tissue cells but not immune cells. So far, IL-22 was known to plays a fundamental role in the elimination of bacterial infections at border surfaces of the body and to protect tissues from damage. This research highlight article arranges the facts regarding the effects of IL-22 in the context of adiposity and metabolic alterations and postulates a new function of the immune system. [ABSTRACT FROM AUTHOR]

Background: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. Methods: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. Results: In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. Conclusions: We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells. [ABSTRACT FROM AUTHOR]

Background: Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism. Results: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (∼600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway. Conclusion: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes. [ABSTRACT FROM AUTHOR]

Background: Fungal skull base osteomyelitis (SBO) is a severe complication of otitis externa or sinonasal infection, and is mainly caused by Aspergillus species. Here we investigate innate and adaptive immune responses in patients with Aspergillus SBO to identify defects in the immune response that could explain the susceptibility to this devastating disease. Methods: Peripheral blood mononuclear cells isolated from six patients with Aspergillus SBO and healthy volunteers were stimulated with various microbial stimuli, among which also the fungal pathogens Candida albicans and Aspergillus fumigatus. The proinflammatory cytokines IL-6, TNFα and IL-1β, and the T-helper cell-derived cytokines IFNγ, IL-17 and IL-22 were measured in cell culture supernatants by ELISA. Results: Proinflammatory cytokine responses did not differ between SBO patients and healthy volunteers. The Candida- and Aspergillus-specific Th17 response (production of IL-17 and IL-22) was significantly decreased in the SBO patients compared to healthy individuals, while Th1 cytokine response (IFNγ production) did not differ between the two groups. Conclusions: We show that patients with Aspergillus skull base osteomyelitis infection have specific defects in Th17 responses. Since IL-17 and IL-22 are important for stimulating antifungal host defense, we hypothesize that strategies that have the ability to improve IL-17 and IL-22 production may be useful as adjuvant immunotherapy in patients with Aspergillus SBO. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease, a common extra-articular complication of connective tissue disease, is characterized by progressive and irreversible pulmonary inflammation and fibrosis, which causes significant mortality. IL-22 shows a potential in regulating chronic inflammation and possibly plays an anti-fibrotic role by protecting epithelial cells. However, the detailed effects and underlying mechanisms are still unclear. In this study, we explored the impact of IL-22 on pulmonary fibrosis both in vivo and in vitro., Methods: To induce pulmonary fibrosis, wild-type mice and IL-22 knockout mice were intratracheally injected with bleomycin followed by treatments with recombinant IL-22 or IL-17A neutralizing antibody. We investigated the role of IL-22 on bleomycin-induced pulmonary fibrosis and the mechanism in the possible interaction between IL-22 and IL-17A. Fibrosis-related genes were detected using RT-qPCR, western blot, and immunofluorescence. Inflammatory and fibrotic changes were assessed based on histological features. We also used A549 human alveolar epithelial cells, NIH/3T3 mouse fibroblast cells, and primary mouse lung fibroblasts to study the impact of IL-22 on fibrosis in vitro., Results: IL-22 knockout mice showed aggravated pulmonary fibrosis compared with wild-type mice, and injection of recombinant IL-22 decreased the severe fibrotic manifestations in IL-22 knockout mice. In cell culture assays, IL-22 decreased protein levels of Collagen I in A549 cells, NIH/3T3 cells, and primary mouse lung fibroblasts. IL-22 also reduced the protein level of Collagen I in NIH/3T3 cells which were co-cultured with T cells. Mechanistically, IL-22 reduced the Th17 cell proportion and IL-17A mRNA level in lung tissues, and treatment with an IL-17A neutralizing antibody alleviated the severe pulmonary fibrosis in IL-22 knockout mice. The IL-17A neutralizing antibody also reduced Collagen I expression in NIH/3T3 cells in vitro. Knockdown of IL-17A with siRNAs or administration of IL-22 in NIH/3T3 cells and MLFs decreased expression of Collagen I, an effect blocked by concurrent use of recombinant IL-17A., Conclusions: IL-22 mediated an anti-fibrogenesis effect in the bleomycin-induced pulmonary fibrosis model and this effect was associated with inhibition of IL-17A., (© 2022. The Author(s).)

Background Interleukin-22 (IL-22) is a member of the IL-10 family of anti-inflammatory cytokines that mediates epithelial immunity. IL-22 expression was found to be increased in patients with ulcerative colitis (UC). Whether genetic polymorphisms of IL-22 also influence UC risk is still unknown. The purpose of this study was to investigate the association between the IL-22 gene polymorphisms (-429 C/T, +1046 T/A and +1995 A/C) and the risk of UC in Chinese Han patients. Methods This hospital-based case-control study comprised 180 patients with UC and 180 age- and gender-matched controls. Genotypes of 3 common polymorphisms of the IL-22 gene were determined by fluorogenic 5' exonuclease assays (TaqMan). Results Patients with UC had a significantly higher frequency of IL-22 -429 TT genotype [odds ratio (OR) =2.43, 95% confidence interval (CI) = 1.35, 4.37; P = 0.003] and -429 T allele (OR =1.54, 95% CI = 1.14, 2.07; P = 0.004) than controls. The findings are still emphatic by the Bonferroni correction. The IL-22 + 1046 T/A and IL-22 + 1995 A/C gene polymorphisms were not associated with a risk of UC. When stratifying by clinical type, location and disease severity of UC, no significant differences were found in any groups. Conclusion This is the first study to provide evidence for an association of IL-22 -429 C/T gene polymorphisms with UC risk. Additional well-designed large studies were required for the validation of our results. [ABSTRACT FROM AUTHOR]

Background: Excessive inflammatory response is the primary cause of early death in patients with endotoxemia. Interleukin 22 (IL-22) has been shown to play critical roles in the modulation of infectious diseases, but its function in regulating immune responses during endotoxemia remains unclear., Methods: Lipopolysaccharide (LPS) was used to induce endotoxemia mouse model with or without a recombinant fusion protein containing human IL-22 (F-652). IL-6, TNF-α, IL-1β, and MCP-1 were measured by ELISA assays. The type of macrophage was assessed by flow cytometry. Real-time PCR was used to detect the expression of S100A9., Results: We found that F-652 injection significantly improved the survival rates and reduced pro-inflammatory cytokines (IL-6, TNF-a, IL-1β, MCP-1) in LPS-induced endotoxemia mice. However, the mice injected with F-652 had a higher number of infiltrated immune cells after LPS treatment, suggesting an impaired immune response. Flow cytometry analysis showed a higher number of F4/80 + Ly6G hi Ly6C hi cells that highly expressed M2-like macrophage markers (Ym1, Arg, CCL17) in the peritoneal cavity of the F-652-treated endotoxemia mice. Further investigation found that these suppressive M2 macrophages might be induced by F-652 since the F-652 treatment could increase S100A9 in vitro., Conclusions: Our study suggests that IL-22 has a protective role against endotoxemia by inducing the development of immunosuppressive cells through S100A9., (© 2022. The Author(s).)

Background: It has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC). Methods: The expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model. Results: Our results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor a1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct- 116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22. Conclusion: In this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation. [ABSTRACT FROM AUTHOR]

Background: Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far. Methods: This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications. Results: A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 ± 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P < 0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P < 0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular (≤18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with reduced overall survival were high CRP (≥2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258, CI (0.077 to 0.862)), model of end stage liver disease (MELD) score ≥20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 0.955, CI (0.922 to 0.989)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)). Conclusions: In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Persistent allergic airway diseases cause a great burden worldwide. Their pathogenesis is not clear enough. There is evidence that one of the recently described cytokine interleukin (IL) 22 may be involved in the pathogenesis of these diseases. Scientists argue if this cytokine acts as proinflammatory or anti-inflammatory agent. The aim of this study was to investigate IL-22 level in patients with persistent allergic airway diseases caused by house dust mite (HDM) in comparison with healthy individuals and to evaluate its relationship with IL-13 and IL-10 level, symptoms score and quality of life., Methods: Patients with persistent allergic rhinitis caused by HDM and having symptoms for at least 2 years with or without allergic asthma were involved into the study. Measurements of IL-22, IL-13 and IL-10 and in serum and nasal lavage was performed by ELISA. Questionnaires assessing symptoms severity and quality of life were used., Results: A tendency was observed that IL-22 in serum and nasal lavage was higher in patients with allergic airway diseases compared to control group (14.86 pg/ml vs. 7.04 pg/ml and 2.67 pg/ml vs. 1.28 pg/ml, respectively). Positive statistically significant correlation was estimated between serum IL-22 and serum IL-10 (rs = 0.57, p < 0.01) and IL-13 (rs = 0.44, p < 0.05) level. Moreover, positive significant correlation was found between IL-22 in nasal lavage and IL-10 in nasal lavage (rs = 0.37, p < 0.05). There was a negative statistically significant correlation between serum IL-22 and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (rs = - 0.42, p < 0.05)., Conclusion: Our study showed a possible anti-inflammatory effect of IL-22 in patients with persistent allergic airway diseases caused by HDM.

Background: The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA)., Methods: Serum from patients with RA and osteoarthritis (OA), and healthy controls, and synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis., Results: Serum and synovial IL-25 levels in RA were upregulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers., Conclusion: In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

Background: The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of nervous system injuries and congenital defects. However, host immunity- and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays, a role in ZIKV infection is unknown., Methods: The cellular source of IL-22 was identified in IFNAR -/- mice and wild-type (WT) neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old WT and IL-22 -/- mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8 + T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, glial cells were cultured in vitro and infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression, and viral loads., Results: We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to exhibit weight loss, staggered steps, bilateral hind limb paralysis, and weakness at 10 days post-infection (dpi) and ultimately succumbed to infection at 16-19 dpi. IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly improved clinical signs of neurological disease and mortality. ZIKV infection also induced the activation of microglia and astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a negligible effect on glial cells in vitro, IL-22 -/- mice mounted more vigorous ZIKV-specific CD8 + T cell responses, which led to a more effective control of ZIKV in the brain., Conclusions: Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

Background: LncRNA LINC00662 is closely related to the occurrence and development of cancer. This study aims to explore the effect of LINC00662 on colon cancer tumor growth and metastasis and its molecular mechanism., Methods: CCK8, colony formation, transwell, scratch wound, TUNEL, flow cytometry, RT-PCR, western blotting and immunohistochemistry assays were used to detect the proliferation, apoptosis, invasion and migration of colon cancer cell and mRNA and protein expressions. Luciferase reporter and RNA pull down assays were used to detect the combination of LINC00662 and miR-340-5p or IL22 and the combination of miR-340-5p and CLDN8/IL22. Co-immunoprecipitation were used to detect the co-expression of CLDN8 and IL22 in colon cell lines. The targets of LINC00662 were predicated by Starbase v2.0. The target genes of miR-340-5p were predicated by miRDB and TargetScan. GO and KEGG enrichment analysis were performed by DAVID website., Results: LINC00662 was up-regulation in colon cancer tissues and cell lines. Univariate Cox regression analysis showed that the LINC00662 expression level was related to the poor prognosis. LINC00662-WT and miR-340-5p mimics co-transfection depressed luciferase activity and IL22/CLDN8-WT and miR-340-5p inhibitors co-transfection memorably motivated luciferase activity. LINC00662 overexpression promoted cell proliferation, invasion and migration, and inhibited cell apoptosis in colon cancer. In vivo xenograft studies in nude mice manifested that LINC00662 overexpression prominently accelerate tumor growth. There was an opposite reaction in the biological functions of colon cells and tumor growth between LINC00662 overexpression and LINC00662 inhibition in vitro and in vivo. The functions of miR-340-5p mimics regulating the biological functions of colon cells and tumor growth were consistent with those of LINC00662 inhibition. CLDN8 and IL22, as target genes of miR-340-5p, reversed the functions of LINC00662 affecting the biological functions of colon cells and the protein levels of Bax, Bcl-2, XIAP, VEGF, MMP-2, E-cadherin and N-cadherin. Co-immunoprecipitation experiments indicated that CLDN8 directly interact with IL22 in colon cell lines. LINC00662 regulated CLDN8 and IL22 expressions and the activation of ERK signaling pathway via targeting miR-340-5p., Conclusion: LINC00662 overexpression promoted the occurrence and development of colon cancer by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway.

Background: Malaria, one of the largest health burdens worldwide, is caused by Plasmodium spp. infection. Upon infection, the host's immune system begins to clear the parasites. However, Plasmodium species have evolved to escape the host's immune clearance. T-cell immunoglobulin and mucin domain 3 (Tim-3), a surface molecule on most immune cells, is often referred to as an exhaustion marker. Galectin (Gal)-9 is a Tim-3 ligand and the T helper (Th) 1 cell response is inhibited when Gal-9 binds to Tim-3. In the present study, dynamic expression of Tim-3 on key populations of lymphocytes during infection periods of Plasmodium berghei and its significance in disease resistance and pathogenesis were explored. Methods: Tim-3 expression on critical lymphocyte populations and the proportion of these cells, as well as the levels of cytokines in the sera of infected mice, were detected by flow cytometry. Further, in vitro anti-Tim-3 assay using an anti-Tim-3 antibody and in vivo Tim-3-Gal-9 signaling blockade assays using α-lactose (an antagonist of Gal-9) were conducted. An Annexin V Apoptosis Detection Kit with propidium iodide was used to detect apoptosis. In addition, proteins associated with apoptosis in lung and spleen tissues were confirmed by Western blotting assays. Results: Increased Tim-3 expression on splenic CD8+ and splenic CD4+, and circulatory CD4+ T cells was associated with a reduction in the proportion of these cells. Furthermore, the levels of interleukin (IL)-2, IL-4, IL-6, IL-22, and interferon (IFN)-γ, but not that of tumor necrosis factor alpha (TNF-α), IL-10, and IL-9, increased to their highest levels at day 4 post-infection and decreased thereafter. Blocking Tim-3 signaling in vitro inhibited lymphocyte apoptosis. Tim-3-Gal-9 signaling blockade in vivo did not protect the mice, but induced the expression of the immunosuppressive molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT), in Plasmodium berghei ANKA-infected mice. Conclusions: Tim-3 on lymphocytes negatively regulates cell-mediated immunity against Plasmodium infection, and blocking Tim-3-galectin 9 signaling using α-lactose did not significantly protect the mice; however, it induced the compensatory expression of TIGIT. Further investigations are required to identify whether combined blockade of Tim-3 and TIGIT signaling could achieve a better protective effect. [ABSTRACT FROM AUTHOR]

Background: It has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation. In the present work, we evaluated inflammatory and pro-oxidant soluble signature in non-syndromic ASD and age-matched typically developing (TD) control children.Methods: We analyzed leukocyte gene expression of inflammatory cytokines and inflammation/oxidative-stress related molecules in 21 ASD and 20 TD children. Moreover, in another-comparable-group of non-syndromic ASD (N = 22) and TD (N = 21) children, we analyzed for the first time the protein expression of the four members of the antioxidant enzyme family of peroxiredoxins (Prx) in both erythrocyte membranes and in plasma.Results: The gene expression of IL6 and of HSP70i, a stress protein, was increased in ASD children. Moreover, gene expression of many inflammatory cytokines and inflammation/oxidative stress-related proteins correlated with clinical features, and appeared to be linked by a complex network of inter-correlations involving the Aryl Hydrocarbon Receptor signaling pathway. In addition, when the study of inter-correlations within the expression pattern of these molecules was extended to include the healthy subjects, the intrinsic physiological relationships of the inflammatory/oxidative stress network emerged. Plasma levels of Prx2 and Prx5 were remarkably increased in ASD compared to healthy controls, while no significant differences were found in red cell Prx levels.Conclusions: Previous findings reported elevated inflammatory cytokines in the plasma of ASD children, without clearly pointing to the presence of neuro-inflammation. On the other hand, the finding of microglia activation in autoptic specimens was clearly suggesting the presence of neuro-inflammation in ASD. Given the role of peroxiredoxins in the protection of brain cells against oxidative stress, the whole of our results, using peripheral data collected in living patients, support the involvement of neuro-inflammation in ASD, and generate a rational for neuro-inflammation as a possible therapeutic target and for plasma Prx5 as a novel indicator of ASD severity. [ABSTRACT FROM AUTHOR]

Background: Persistent levels of low-grade inflammation and T lymphocyte activation are associated with insulin resistance and type 2 diabetes that eventually lead to the development of cardiovascular diseases. Interestingly, increasing studies report on an emerging role of innate lymphoid cells in the development of both type 2 diabetes and cardiovascular disease. This systematic review will provide a comprehensive synthesis of available studies reporting on the role of innate lymphoid cells and associated T helper cell function in type 2 diabetic patients. It will further provide insight into the association of innate lymphoid cell activation and cardiovascular risk in adults living with type 2 diabetes. Methods: This systematic review protocol has been prepared in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines. The protocol has been registered with PROSPERO (CRD42018106159). This systematic review and meta-analysis will include published randomised clinical trials, observational studies, and case-control studies. We will also include grey literature. A search strategy will be developed with the help of subject librarian using Medical Subject Heading (MeSH) words for MEDLINE. This will then be adapted for the Embase database. Two independent reviewers VM and BBN will screen all studies using prespecified inclusion and exclusion criteria. The Downs and Black checklist will be used to assess the quality of individual studies. Predefined relevant data items will be extracted using sheets, and all study tables will be created using Review Manager V.5.3. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to assess the strength of evidence. Ethics and dissemination: The review will include publicly available data. The findings of this review will be disseminated through publications. [ABSTRACT FROM AUTHOR]

Background: This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients.Methods: 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively.Results: PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival.Conclusions: Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT - Napoli - 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. The IL-17 cytokine family is well known to play important roles in the host defense against bacterial infections at the mucosa. Previously, we reported the potential role of IL-17A in clearing an ETEC infection in piglets. IL-17C, another member of the IL-17 family, is highly expressed in the intestinal epithelium, however, its role during an ETEC infection is still unclear. In this study, we demonstrate that F4+ ETEC induce IL-17C mRNA and protein expression in intestinal tissues as well as in porcine intestinal epithelial cells (IPEC-J2). This IL-17C production is largely dependent on TLR5 signaling in IPEC-J2 cells. Both F4+ ETEC infection and exogenous IL-17C increased the expression of antimicrobial peptides and tight junction proteins, such as porcine beta-defensin (pBD)-2, claudin-1, claudin-2 and occludin in IPEC-J2 cells. Taken together, our data demonstrate that TLR5-mediated IL-17C expression in intestinal epithelial cells enhances mucosal host defense responses in a unique autocrine/paracrine manner in the intestinal epithelium against ETEC infection. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134 + and PD-1 + T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134 + and PD-1 + CD4 + T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients., Methods: Peripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134 + and PD-1 + T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index., Results: Peripheral unstimulated CD134 + and PD-1 + CD4 + T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134 + and PD-1 + CD4 + T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134 + CD4 + T-cells were also significantly decreased in SLE as compared to HC., Conclusion: CD134 + and PD-1 + CD4 + T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.

Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) is highly expressed on macrophages in inflamed intestines and reportedly promotes inflammatory bowel disease (IBD) by augmenting pro-inflammatory responses. To study the mechanism mediated by TREM-1 on macrophages, we generated an independent TREM-1 deficient mouse., Methods: Acute colitis was induced in C57BL/6 and TREM-1-deficient mice by the administration of dextran sodium sulfate (DSS). Colonic lamina propria immune cell composition and cytokines were analyzed. An innate lymphoid cell (ILC) co-culture experiment with macrophages was used to analyze IL-22 levels. Exogenous IL-22 and TREM-1-expressing macrophages were supplied to TREM-1-deficient mice for examining their effects on intestinal barrier integrity., Results: In inflamed colons, TREM-1 loss compromised the activation of ILC3 and their production of IL-22, which is required for intestinal barrier integrity. ILC3-mediated IL-22 production depends on IL-1β secreted by M1-polarized macrophages, and we found that TREM-1 deficiency results in a decreased number of IL-1β producing-M1 macrophages in colons exposed to DSS. Accordingly, DSS-mediated damage was ameliorated by supplying exogenous IL-22 and TREM-1-expressing macrophages to TREM-1-deficient mice., Conclusions: TREM-1 plays a crucial role in regulating IL-22 production by ILC3 through modulating M1-macrophage polarization during DSS-induced acute colitis.

An elevation of serum inflammatory biomarkers in achalasia patients compared with controls recently was demonstrated. It has not been determined whether the elevation of inflammatory cytokines is unique to achalasia or occurs with other diseases involving the esophagus. The primary aim of our study was to compare the differences in plasma immunological profiles (TNF- α receptor, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23) of patients with achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD). A secondary aim of this study was to classify these same plasma cytokine profiles in the three achalasia subtypes., Methods: Plasma from 53 patients with achalasia, 22 with EoE, and 20 with GERD (symptoms plus esophagitis or + reflux study) were analyzed., Exclusion Criteria: malignancy, autoimmune condition, immunodeficiency disorder, and treatment with steroids/immune modulating drugs. Cytokine levels were assayed via multiplex enzyme-linked immunosorbent assay (ELISA)., Results: Our key finding revealed significant elevations in IL- 6 (p = 0.0158) in achalasia patients compared with EoE patients. Overall, plasma inflammatory biomarker patterns were not different in the three subtypes of achalasia., Conclusion: There were no differences between the cytokine levels of any of the measured biomarkers between the achalasia and GERD groups suggesting that luminal stasis does increase biomarker levels for any of the cytokines examined in our study. While these results are an early first step towards clarifying some aspects of the pathogenesis of achalasia, they bring about many more questions that require further investigation and expansion. Further investigation with a larger cohort and a broader panel of biomarkers is needed.

Background: IL-17 and IL-22 cytokines play an important role in protective immune responses against Mycobacterium tuberculosis (Mtb) infection. Information on the production of these cytokines and the factors that regulate their production in the context of human immunodeficiency virus (HIV) and latent tuberculosis infection (LTBI) or active tuberculosis disease (ATB) is limited. In the current study, we compared the production of these two cytokines by PBMC of HIV-LTBI+ and HIV + LTBI+ individuals in response to Mtb antigens CFP-10 (culture filtrate protein) and ESAT-6 (Early Secretory Antigenic Target). We also determined the mechanisms involved in their production., Methods: We cultured Peripheral Blood Mononuclear Cells (PBMCs) from HIV- individuals and HIV+ patients with latent tuberculosis and active disease with CFP-10 and ESAT-6. Production of IL-17, IL-22 and PD1 (Programmed Death 1), ICOS (Inducible T-cell Costimulator), IL-23R and FoxP3 (Forkhead box P3) expression on CD4+ T cells was measured., Results: In response to Mtb antigens CFP-10 and ESAT-6, freshly isolated PBMCs from HIV+ LTBI+ and HIV+ active TB patients produced less IL-17 and IL-22 and more IL-10, expressed less IL-23R, and more PD1 and expanded to more FoxP3+ cells. Active TB infection in HIV+ individuals further inhibited antigen specific IL-17 and IL-22 production compared to those with LTBI. Neutralization of PD1 restored IL-23R expression, IL-17 and IL-22 levels and lowered IL-10 production and reduced expansion of FoxP3 T cells., Conclusions: In the current study we found that increased PD1 expression in HIV + LTBI+ and HIV+ active TB patients inhibits IL-17, IL-22 production and IL-23R expression in response to Mtb antigens CFP-10 and ESAT-6.

Background: Interleukin-22 (IL-22) plays a prominent role in epithelial regeneration and dampening of chronic inflammatory responses by protecting intestinal stem cells from immune-mediated tissue damage. IL-22 has a considerable therapeutic potential in graft-versus-host disease (GVHD), which is a frequent and challenging complication following allogeneic stem cell transplantation. The aim of our study was to engineer Lactobacillus for delivery of IL-22 directly to the intestinal mucosa as a new therapeutic strategy for GVHD., Results: The secretion and surface anchoring of mouse IL-22 by Lactobacillus paracasei BL23 was demonstrated by Western blot and flow cytometry. Both secreted and anchored mouse IL-22 produced by Lactobacillus was biologically active, as determined by its ability to induce IL-10 secretion in the Colo 205 human colon cancer cell line., Conclusions: We have demonstrated the secretion and surface anchoring of bioactive IL-22 by Lactobacillus. Our results suggest that IL-22 expressing lactobacilli may potentially be a useful mucosal therapeutic agent for the treatment of GVHD, provided that chromosomal integration of the IL-22 expression cassettes can be achieved.

Background: Children are prone to get infections, especially in the respiratory system and the gut mainly because their immune system is immature. T cells significantly contribute to the prevention of infections, and different helper T cell (Th) subsets play different anti-pathogen roles. Interleukin (IL)-22 producing by T-helper 22 cells (Th22) play an important role in host defense against Gram-negative bacterial organisms in gut and lung. T-helper 17 cells (Th17) protect against extracelluar bacteria and fungi especially at the epithelial surface. However, there is no report comparing IL-22 producing T cells and Th17 cells in healthy young children to adults., Methods: Flow cytometry (FCM) was used to observe whether Th22 subset existed in the peripheral blood of healthy young children. Meanwhile, we determined the frequencies of Th subsets including Th17, Th1 and Th2, cytotoxic T (Tc)1 subset, CD4+ and CD8+ memory T cells in the peripheral blood of both young children and adults., Results: In the present study, we demonstrated that Th22 subset existed in peripheral blood of children, with IL-22 mainly secreted by CD4 + CD45RO+ memory T cells. Moreover, we observed that IL-22 + CD4 + T cells and Th subsets including Th17, Th1, and Th2 frequencies of young children (1-6 years old) were significantly lower than adults. While the Th1 frequency from Group A (1-3 years old) was markedly lower than that from Group B (4-6 years old). No significant differences of Th17 or IL-22 + CD4 + T cells frequencies were observed between these two groups. In addition, Tc1 subset frequencies were also remarkably lower in young children than in adults. Furthermore, lower frequencies of CD45RO+ memory CD4+ and CD8+ T cells in young children than in adults, and significant correlation between CD45RO+ memory CD4 + T cells and IL-22 + CD4 + T cells, Th1, Th17 were observed., Conclusions: Th22 subset exists in the peripheral blood of young children. Compared with adults, there are lower frequencies of IL-22 + CD4 + T cells, as well as Th1, Th17, Th2 and Tc1 subsets in the peripheral blood of young children.

Background: Recently, it is found that T-helper (Th) 22 cells are involved in different types of autoimmune and tumor diseases. But, till now, no study has been carried out to understand the involvement of these cells in cervical cancer (CC)., Methods: Flow cytometry was used to determine the expression of interferon gamma (IFN-γ), Interleukin-22 (IL-22), IL-17 in the peripheral blood of healthy controls (HC), CIN and cervical cancer patients. From peripheral blood mononuclear cells (PBMCs), mRNA expression levels of Aryl hydrocarbon receptor (AHR), RAR-related orphan receptor C (RORC), TNF-α and IL-6 were respectively determined. Using the method of ELISA, plasma concentrations of IL-22, IL-17 and TNF-α were examined., Results: Th22 and Th17 cells were elevated in CC and CIN patients. Th1 cells and the plasma concentrations of IL-22 in CC patients were significantly increased compared with HC. In CC patients, an increased prevalence of Th22 cells was associated with lymph node metastases. There was a positive correlation between Th22 and Th17 cells, but an approximately negative correlation between Th22 and Th1 cells in CC patients. The mRNA expression of RORC, TNF-α and IL-6 was significantly high in CC patients., Conclusions: Our results indicate that there is a higher circulatory frequency of Th22, Th17 and Th1 cells in CC which may conjointly participate in the pathogenesis and growth of CC.