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Rationale: The role of the innate immune system in polycystic liver disease (PLD) has been underexplored despite its potential importance in disease progression. This study explores the innate immune response in PLD patients by analyzing cytokine production of peripheral blood mononuclear cells (PBMCs) in response to various pathogens compared to healthy controls., Methods: Samples were collected from patients with ADPLD or ADPKD and PLD. PBMCs were isolated and stimulated with LPS (1 ng), LPS (10 ng), E. coli, K. pneumoniae, S. aureus, and C. albicans. ELISA was used to measure TNF, IL-1β, IL-1Ra, IL-6, and IL-8 concentrations after 24 hours, and IL-17, IL-22, and IFNγ concentrations after 7 days. Control samples were matched for age and gender., Results: 104 patients and 12 controls were included. PLD patients showed consistent increased IL-6 concentrations compared to controls. Other cytokine levels varied per stimulus. Controls showed higher IL-8 and TNF concentrations in response to Gram-negative bacteria, while PLD patients showed higher IL-1β and IL-1Ra levels in response to S. aureus and C. albicans. No clear differences were found in IL-17, IL-22, and IFN-γ concentrations after 7 days. These observed differences were independent of demographic and clinical parameters., Conclusion: Compared to healthy controls, the PLD patients innate immune system shows an altered response when stimulated by various pathogens. These findings underscore the importance of further investigation into the underlying mechanisms as this might help our understanding disease progression and be a potential target for new therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dysregulation of cytokines and intestinal mycobiome has been surveyed in the progression of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD). On the other hand, the intestinal fungal flora and its main receptor, Dectin-1, induce immune-derived cytokines., Methods: Total 64 individuals comprising 32 patients with UC (case group) and 32 healthy subjects (HS group) were assessed. The type and prevalence of fecal yeast species were determined by deoxyribonucleic acid (DNA) sequencing through polymerase chain reaction (PCR) amplification using ITS4 and ITS5 primers. Furthermore, the ribonucleic acid (RNAs) of IL-4, IL-10, IL-17, IL-22 and IFN-γ were extracted. The expression of Dectin-1 gene was then measured in the excised tissue samples., Results: A higher global fungal load in UC-affected patients (75%) was found in comparison with the HS group (25%), especially Candida albicans. Saccharomyces cerevisiae was significantly reduced in the fecal samples of UC-affected patients compared to HS (15.04% vs. 1.93% UC). The expression level of Dectin-1 was significantly elevated in patients with active UC (7.37 ± 0.81) than in patients with non-active UC (5.01 ± 77.25) and healthy controls (0.97 ± 0.24) (p < 0.05). The expression levels of IL-4, IL-10, especially both IL-17 and IL-22, were higher in the active UC group compared to the HS group (p = 0.0101, p = 0.0155, p < 0.0001, p < 0.0001, respectively). Similar expression level of IL-4, IL-10, IL-17, IL-22 (p > 0.999) and lower expression of interferongamma (IFN-γ) (p = 0.0021) were found in the non-active UC group compared to the HS group. A significant weak to moderate correlation was detected between Dectin-1 and IL-17 (r = 0.339, p = 0.019), as well as Dectin-1 and IL-22 (r = 0.373, p = 0.015). Furthermore, the expression levels of Dectin-1, IL-17 and IL-22 displayed significant associations with disease activity (p < 0.001, p = 0.029 and p = 0.003, respectively), regardless of the participant group., Conclusions: The current study revealed a possible role for intestinal fungi to promote colonic inflammation and increase UC activity through Dectin-1 stimulation. A positive correlation was detected between intestinal fungal richness with UC susceptibility and activity. IL-4 and IL-10 were associated with disease activity. Besides, the expression levels of Dectin-1, IL-17 and IL-22 were independently associated with disease activity., (© 2024. Indian Society of Gastroenterology.)

Mycobacterium avium subsp. hominissuis (MAH) is a common environmental bacterium that causes infection in immunocompromised patients such as those with HIV/AIDS, or patients with chronic lung disease such as cystic fibrosis. There are many strains of MAH with varying levels of virulence. Infection with MAH strains 100 and 104 has been associated with different immune responses in mice and outcome of the disease. While MAH 100 infection tends to be cleared from mice, MAH 104 is virulent and grows in host tissue. What is currently unknown are the mechanisms related to this difference in host defense and virulence. Our hypothesis is that differences in circulating innate lymphocytes response are associated with increased protection from infection. Innate lymphoid cells (ILC) are lymphoid cells with an important role in regulation of innate immune systems. ILCs can be categorized into three subpopulations ILC1, ILC2, and ILC3 based on their cytokine production and regulatory transcription factors. Investigation was carried out on how macrophage anti-MAH response change depending on activation by primary mouse lymphocytes activated with IL-12, IL-33, and IL-23, triggering differentiation into ILC-like subpopulations. Our results do not affirm the role of any one ILC subpopulation in macrophage anti-M. avium ability. Our findings instead support the conclusion that MAH infection of macrophages suppresses the stimulatory function of ILCs., (© 2023. The Author(s).)

Objective: To investigate the effects of secukinumab treatment for psoriasis on different functional cytokines and inflammatory mediators in patients' serum METHODS: Enzyme-linked immunosorbent assay was used to detect interleukin (IL)-1β and IL-1RA associated with intrinsic immunity; IL-6, IL-18, and growth regulated oncogene alpha (GROα) associated with neutrophils; IL-12, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ associated with Th1; IL-23, IL-17A, and IL-22 associated with Th17; Thymus activation regulated chemokine (TARC), IL-13, and defensin beta 2 (DEFB2) associated with Th2; Vascular endothelial growth factor (VEGF)-A and IL-10 associated with angiogenesis; and IFN-γ associated with sepsis in the peripheral blood of 12 patients with common psoriasis treated with secukinumab and 15 healthy controls. IL-23, IL-17A, IL-22 associated with Th17; TARC, IL-13, DEFB2 associated with Th2; VEGF-A, IL-10 associated with angiogenesis and procalcitonin (PCT) associated with sepsis. The differences in expression of the above cytokines before and after treatment and the correlation with psoriasis disease severity［Psoriasis Area Severity Index(PASI) score］, age, and disease duration were analyzed., Results: The mean PASI score of the enrolled patients with moderate to severe psoriasis was 21.6 ± 11.0 before treatment and decreased to below 1 after treatment. Serum IL-6; IL-18, GROα, IFN-γ, TNF-α, VEGF-A, and IL-17A were significantly higher than normal. And IL-17A and IFN-γ were positively correlated with disease duration and age, and IL-18 was positively correlated with PASI score. The expression levels of IL-6, GROα, VEGF-A, IFN-γ, TNF-α, IL-17A and IL-23 were significantly lower after secukinumab treatment compared with those before treatment, but the expression levels of IFN-γ, VEGF-A, TARC, IL-13, and DEFB2 were still significantly higher than those of normal subjects after treatment CONCLUSIONS: secukinumab clears skin lesions by antagonizing IL-17A and simultaneously decreasing the expression levels of IL-6, GRO α, VEGF-A, IFN-γ, TNF-α, IL-17A, and IL-23., (© 2023 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2 - Paneth cells were localized in the duodenum, whereas the majority of Fut2 + Paneth cells were in the ileum. Fut2 + Paneth cells showed higher granularity and structural complexity than did Fut2 - Paneth cells, suggesting that Fut2 + Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2 + Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2 + Paneth cells as part of gut defense., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Considering the collaboration between immune responses and medications for the improvement of visceral leishmaniasis (VL), this study investigated the levels of T helper (Th) 22 and the corresponding cytokines in the acute phase of VL and their alterations following treatment. The study was conducted on 18 patients with confirmed VL and 20 healthy sex and age matched children as the controls. The levels of Th22 cells and the cytokines driving their differentiations and functions in the blood and peripheral blood mononuclear cells (PBMC) cultured supernatants, were assessed using flow cytometry method. The results revealed significantly higher levels of Th22, IL-21 and IL-6 in the patients' blood than those in the controls. Additionally, higher levels of IL-21 and IL-22 were observed in the cultured supernatants of VL patients' PBMCs, compared to the controls. Upon treatment, Th22 and IL-6 were down-regulated and conversely, IL-21, IL-22, IL-23 and IL-33 were significantly up-regulated in the patients' blood at different time points. Receiver operating characteristic (ROC) curve analysis indicated that for the differential diagnosis of VL, plasma IL-21 is more sensitive and specific than Th22 and the above mentioned cytokines. The higher proportions of Th22 and IL-21 in the VL patients and their alterations post treatment confer their roles in the immunopathogenesis of VL. So, Th22 and IL-21 in the patients' blood can be considered as biomarkers to be used for the differential diagnosis of VL. Nevertheless, further studies are warranted to clarify their particular mechanisms in this process., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Hepatitis C virus (HCV) is the leading cause of chronic liver diseases including hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. We aimed to assess serum levels of interleukin (IL)-22, IL-27 and IL-35 in patients with hepatitis C and healthy controls to investigate their possible relationship with viral genotypes and liver enzyme levels., Method: A total of 30 newly diagnosed hepatitis C patients with no history of antiviral therapy and 30 healthy individuals participated in this study. Serum levels of IL-22, IL-27 and IL-35 were determined by ELISA in peripheral blood samples from patients prior to and following treament with pan-genotypic direct-acting anti-viral therapy. Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were measured to determine any possible association between hepatic enzymes and cytokine serum levels concentrations., Result: The results show elevated serum levels of of IL-35 in HCV-infected patients compared to treated cases and healthy controls, whereas there was no significant difference in IL-22 and IL-27 serum levels among the three groups. Additionally, the cytokine levels were not significantly correlated with certain genotypes and levels of liver enzymes., Conclusion: Our findings indicate a potential role for IL-35 in chronic HCV infection and therapeutic management of patients with hepatitis C infection.

The α-L-guluronic acid (G2013), is a novel immunosuppressive drug (PCT/EP2017/067920). One of the most popular ideas in designing drugs for multiple sclerosis (MS) is to restrict the main inflammation-related lymphocytes and cytokines. The foremost problems with conventional drugs are their side effects and low efficacy. In order to rectify these problems, we examined the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, in MS patients PBMCs. RNA was extracted from peripheral blood mononuclear cell (PBMC) of 12 relapsing-remitting MS patients and 12 healthy volunteers and the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, were assessed by real-time PCR. Overall, the results show that G2013 is able to significantly reduce the gene expression of IL-22, AHR, RORC, and T-bet. Collectively, G2013 might be considered and studied as a new drug of possible use to MS patients due to its immunosuppressive property on some of the main inflammatory cytokine and transcription factors., (© 2020 Wiley Periodicals, Inc.)

T helper-17 (Th17) cells, which mainly produce IL-17, are associated with development of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and psoriasis. IL-17 and related cytokines are therapeutic targets of these diseases. In atopic dermatitis (AD), Th2 cytokines such as IL-4 and IL-13 are regarded to be the main player of the disease; however, Th17 cytokines are also expressed in AD skin lesions. Expression of IL-22 rather than IL-17 is predominant in AD skin, which is contrary to cytokine expression in psoriasis skin. Relatively low IL-17 expression in AD skin can induce relatively low antimicrobial peptide expression, which may be a reason why bacterial infection is frequently seen in AD patients. Failure of clinical trials for investigating the efficacy of anti-IL-12/23 p40 in AD has suggested that IL-17 expressed in skin lesions should not be the main player but a bystander responding to barrier dysfunction.

Background: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored., Objective: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects., Methods: Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4 + /CD8 + T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA) + versus systemic/CLA - T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies., Results: Although CLA + T H 1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA + T H 2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA - T H 2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22)., Conclusions: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The mammalian intestine is colonized by over a trillion microbes that comprise the "gut microbiota," a microbial community which has co-evolved with the host to form a mutually beneficial relationship. Accumulating evidence indicates that the gut microbiota participates in immune system maturation and also plays a central role in host defense against pathogens. Here we review some of the mechanisms employed by the gut microbiota to boost the innate immune response against pathogens present on epithelial mucosal surfaces. Antimicrobial peptide secretion, inflammasome activation and induction of host IL-22, IL-17, and IL-10 production are the most commonly observed strategies employed by the gut microbiota for host anti-pathogen defense. Taken together, the body of evidence suggests that the host gut microbiota can elicit innate immunity against pathogens.

Objective: To investigate the effect of tetrandrine (Tet) on HaCaT cell proliferation and cytokine expression induced by interleukin (IL)-22, and to investigate the underlying mechanism., Methods: The half maximal inhibitory concentration (IC50) and antiproliferation effects of Tet on IL-22-treated HaCaT cells were analysed by MTT assay. Signal transducer and activator of transcription 3 ( STAT3) expression was measured by reverse transcription plus real-time quantitative polymerase chain reaction (qPCR) and by Western blot. Phosphorylated (p)-STAT3 levels were also measured by Western blot. Cytokine production by HaCaT cells was analysed by enzyme-linked immunosorbent assay (ELISA) following administration of IL-22 and/or Tet., Results: Tet displayed a dose-dependent inhibitory effect on HaCaT cell proliferation and reduced the phosphorylation level of STAT3 induced by IL-22, without affecting STAT3 mRNA and protein levels. Furthermore, co-incubation with Tet significantly down-regulated HaCaT cell production of tumour necrosis factor (TNF)-α, IL-1β, IL-6, IL-20 and chemokine (C-C motif) ligand 20 (CCL20) induced by IL-22., Conclusions: Tet inhibits proliferation and cytokine production in HaCaT cells, and the process may involve the inhibition of STAT3 phosphorylation.

Humans are constantly exposed to the opportunistic mold Aspergillus fumigatus , and disease caused by this pathogen is often determined by the magnitude of local and systemic immune responses. We have previously shown a protective role for interleukin-22 (IL-22) after acute A. fumigatus exposure. Here, employing IL-22 Cre R26R eYFP reporter mice, we identified iNKT cells, γδ T cells, and type 3 innate lymphoid cells (ILC3s) as lung cell sources of IL-22 in response to acute A. fumigatus exposure. As these cells often utilize common γ-chain cytokines for their development or maintenance, we determined the role of IL-7, IL-21, and IL-15 in lung IL-22 induction and A. fumigatus lung clearance. We observed that IL-7, IL-21, and IL-15 were essential for, partially required for, or negatively regulated the production of IL-22, respectively. Deficiency in IL-7 and IL-21, but not IL-15R, resulted in impaired fungal clearance. Surprisingly, however, the absence of IL-7, IL-21, or IL-15R signaling had no effect on neutrophil recruitment. The levels of IL-1α, an essential anti- A. fumigatus proinflammatory cytokine, were increased in the absence of IL-7 and IL-15R but decreased in the absence of IL-21. IL-7 was responsible for maintaining lung iNKT cells and γδ T cells, whereas IL-21 was responsible for maintaining lung iNKT cells and ILC3s. In contrast, IL-15R deficiency had no effect on the absolute numbers of any IL-22 cell source, rather resulting in enhanced per cell production of IL-22 by iNKT cells and γδ T cells. Collectively, these results provide insight into how the IL-22 response in the lung is shaped after acute A. fumigatus exposure., (Copyright © 2018 American Society for Microbiology.)

COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow. It is mainly associated with exposure to cigarette smoke. In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide. Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells. Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways. The aims of these molecules are differentiation, proliferation and recruitment of neutrophils. Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight. In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract. Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The importance of cytokines in disc degeneration is well recognized. Little is known about IL-22 expression in the human intervertebral disc. We investigated IL-22 immuno-localization in disc tissue, and molecular expression and production of IL-22 by annulus cells cultured in three-dimensional (3D) culture. We examined human disc tissue using immunohistochemistry and we cultured isolated annulus cells in 3D to analyze IL-22 expression and production, and its receptor, IL-22R, in conditioned media. Ingenuity pathway analysis (IPA) also was used to identify significant gene expression networks within the molecular data. IL-22 and IL-22R were immunolocalized in many cells in the human outer and inner annulus; fewer cells exhibited localization in the nucleus. Three-dimensional culture of annulus cells demonstrated production of IL-22 in conditioned media; exposure to IL-1ß or TNF-α significantly reduced IL-22 levels. Significant decreases also were identified in conditioned media assayed for IL-22R in TNF-α treated cells. IPA analysis showed that IL-22 ranked among the top canonical pathways. We found constitutive expression and production of IL-22 and IL-22R in the disc, which expands our understanding of the effect of pro-inflammatory cytokines on IL-22 expression and production. Three-dimensional cultured annulus cells exposed to IL-1ß or TNF produced significantly lower levels of IL-22 into their conditioned media compared to levels produced by control cells. Our findings have clinical relevance because of the elevated pro-inflammatory milieu within the degenerating human disc.

T helper type 17 (Th17) cells have been shown to be pathogenic in autoimmune diseases; however, their role in type 1 diabetes (T1D) remains inconclusive. We have found that Th17 differentiation of CD4(+) T cells from BDC2·5 T cell receptor transgenic non-obese diabetic (NOD) mice can be driven by interleukin (IL)-23+IL-6 to produce large amounts of IL-22, and these cells induce T1D in young NOD mice upon adoptive transfer. Conversely, polarizing these cells with transforming growth factor (TGF)-β+IL-6 led to non-diabetogenic regulatory Th17 (Treg 17) cells that express high levels of aryl hydrocarbon receptor (AhR) and IL-10 but produced much reduced levels of IL-22. The diabetogenic potential of these Th17 subsets was assessed by adoptive transfer studies in young NOD mice and not NOD.severe combined immunodeficient (SCID) mice to prevent possible transdifferentiation of these cells in vivo. Based upon our results, we suggest that both pathogenic Th17 cells and non-pathogenic regulatory Treg 17 cells can be generated from CD4(+) T cells under appropriate polarization conditions. This may explain the contradictory role of Th17 cells in T1D. The IL-17 producing Treg 17 cells offer a novel regulatory T cell population for the modulation of autoimmunity., (© 2015 British Society for Immunology.)

Background: Infections by Helicobacter can cause the stimulation of sophisticated immune response in mucosal immunity. Among the different lymphocytes, Th17 plays an important role in the defense against H. pylori and may cause gastritis and peptic ulcer due to the increased activation of Th17 and cytokine changes., Aim: To find a relationship between Th17 and IL-17A, IL-21, IL-22, IL-23, TGF-β in the patients with H. pylori infection having signs including gastritis and peptic ulcer., Methods: A total of 36 samples from the patients [24 Hp+ and 12 Hp- cases] with dyspepsia symptoms were collected. The percentage of Th17 was measured by flow cytometry. The levels of Th17-associated cytokines in the sera and supernatants of peripheral blood mononuclear cells (PBMCs) which were stimulated with the H. pylori antigen, phytohemagglutinin (PHA), or Dynabeads were measured by ELISA., Results: Patients were divided into two groups of having either H. pylori infected (peptic ulcer, gastritis (mild, moderate)) or being uninfected. The percentage of Th17 in the patients with peptic ulcer and gastritis was significantly higher than their uninfected counterparts (p ≤ .001). The serum levels of IL-17A, IL-23, and TGF-β in the peptic ulcer and gastritis groups were significantly higher compared with the corresponding levels in the uninfected population (p < .05). A significant association of TGF-β, IL-21, and Th17 was observed with low levels of IL-17A in the mild gastritis patients (p < .05). Significantly higher levels of IL-22, IL-17A, IL-23, and higher Th17 frequencies were detected in the moderate gastritis patients, as compared with the uninfected patients (p ≤ .001)., Conclusion: It can be concluded that among the cytokines associated with Th17, the two cytokines of IL-21 and TGF-β play a more critical role in peptic ulcer and gastritis in the individuals infected with H. pylori. Furthermore, inflammation varies depending on the type of the cytokine and its secreted level., (© 2015 John Wiley & Sons Ltd.)

Despite the increasing incidence of the Candida parapsilosis complex in the clinical setting and high mortality rates associated with disseminated infection, the host-fungus interactions regarding Candida parapsilosis sensu stricto and the closely related species C. orthopsilosis and C. metapsilosis remains blurred. In this study, we analyzed inflammatory cytokines levels and histopathology as well as fungal burden in spleen, kidney and lung of mice infected with six strains of the "psilosis" group with different enzymatic profiles. Strong interleukin 22 (IL-22) and tumor necrosis factor α (TNF-α) responses were observed in analyzed organs from infected mice (P < .0001) regardless of the species and enzymatic profile. TNF-α and IL-22 levels were related with spleen inflammation and fungal load. Fungal cells were detected only in spleen and kidney of infected mice, especially by day 2 post-challenge. The kidney showed glomerular retraction and partial destruction of renal tubules. Our data suggest that a strong inflammatory response, mainly of IL-22 and TNF-α, could be involved in Candida parapsilosis complex infection control., (© The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues., (© Society for Leukocyte Biology.)

The link between chronic inflammation and cancer has long been suspected, due to the pioneering work of Rudolf Virchow over 150 years ago. Yet the causal relationship between inflammation and cancer was only deciphered in the past decade or so, using animal models of various cancers. Up to 20% of all human cancers result from chronic inflammation and persistent infections. Proinflammatory cytokines and tumor-infiltrating myeloid and immune cells play critical roles in almost every developmental stages of inflammation-induced cancers, from initiation, promotion, and progression to malignant metastasis. However, even in cancers with no preceding inflammation, inflammatory cells infiltrate tumor stroma and contribute to cancer development. Such "tumor-elicited inflammation" further emphasizes the importance of inflammation in different types of cancers, including that of the colon. In this review, we summarize our current knowledge of the function and induction mechanisms of inflammatory cytokines during colorectal cancer development, and hope to provide insight into the development of novel anticancer therapies by modulating tumor-elicited inflammation., (© 2015 Elsevier Inc. All rights reserved.)

Studies about thymic B cells are scarce in the literature, but it was suggested that they can exert modulatory and regulatory functions on the immune system. Thymic B cells can play some role in regulating the most frequent allergic background worldwide, the atopy induced by the mite Dermatophagoides pteronyssinus (Der p). Here, we aimed to evaluate if the polyclonal IgG repertoire produced by Der p-atopic individuals can influence the homing and cytokine profile of human thymic B derived from non-atopic children aged less than seven days. With this purpose, we produced polyclonal IgG formulations and cultivated human thymocytes in their presence. We also assessed IgG subclasses and the direct interaction of IgG with thymic B cell membranes. Our results could demonstrate that Der p-atopic IgG could not reduce the expression of α4β7 homing molecule as observed in response to the other IgG formulations and could reduce the frequency of IFN-γ- and IL-9-producing thymic B cells compared to the mock condition. Der p-atopic IgG could also induce thymic IL-10-producing B cells compared to control conditions. The IgG derived from Der p-atopic individuals failed to diminish the population of IL-13-producing thymic B cells, unlike the reduction observed with other IgG formulations when compared to the mock condition. All IgG formulations had similar levels of IgG subclasses and directly interacted with thymic B cell membranes. Finally, we performed experiments using peripheral non-atopic B cells where IgG effects were not observed. In conclusion, our observation demonstrates that IgG induced in allergic individuals can modulate non-atopic thymic B cells, potentially generating thymic B cells prone to allergy development, which seems to not occur in mature B cells. [ABSTRACT FROM AUTHOR]

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2- Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2- Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.

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. [ABSTRACT FROM AUTHOR]

Dupilumab has revolutionized the treatment of atopic dermatitis. However, not all patients respond optimally, and this may relate to underlying molecular heterogeneity. Nevertheless, clinically useful and accessible methods to assess such heterogeneity have not been developed. We assessed whether cytokine staining and/or histologic features correlate with clinical response to dupilumab in patients with eczematous dermatitis. We retrospectively analyzed biopsies from 61 patients with eczematous dermatitis treated with dupilumab (90.2% met Hanifin-Rajka criteria for atopic dermatitis). RNA in situ hybridization was used to measure markers of type 2 (interleukin [IL]4 , IL13), type 1 (interferon gamma) and type 3 (IL17A, IL17F, IL22) inflammation. Histologic features were also assessed. Patterns were compared among complete (n = 16), partial (n = 37), and nonresponders (n = 8) to dupilumab. We found that increased IL13 expression was associated with optimal response to dupilumab. In contrast, nonresponders tended to express less IL13 and relatively greater levels of type 1 and 3 cytokines. In addition, certain histologic features tended to correlate with improved response to dupilumab. Retrospective approach and small size of the nonresponder group. Cytokine RNA in situ hybridization may aid in treatment selection for eczematous disorders. Moreover, personalization of treatment selection for inflammatory skin diseases may be possible. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD), including Ulcerative Colitis (UC) and Crohn's disease (CD), are inflammatory conditions of the intestinal tract that affect women in their reproductive years. Pregnancy affects Th1- and Th2-cytokines, but how these changes occur during pregnancy in IBD is unclear. We performed a longitudinal profiling of serum cytokines in a cohort of 11 healthy pregnant women and 76 pregnant women with IBD from the first trimester of pregnancy to the first 12 months post-partum. Participants were monitored for biochemical disease activity (C-reactive protein [CRP] and fecal calprotectin [FCP]) and clinical activities. Maternal cytokines were measured using ELISA. We identified changes in Th1 and Th17 cytokines throughout pregnancy in healthy pregnant women. During pregnancy, maternal serum cytokine expressions were influenced by IBD, disease activity, and medications. Active UC was associated with an elevation in IL-21, whereas active CD was associated with elevated IFN-γ, IL-6, and IL-21. Interestingly, T1 serum cytokine levels of IL-22 (>0.624 pg/mL) and IL-6 (>0.648 pg/mL) were associated with worse IBD disease activity throughout pregnancy in women with UC and CD, respectively. This shows serum cytokines in pregnancy differ by IBD, disease activity, and medications. We show for the first time that T1 IL-22 and IL-6 correlate with IBD disease course throughout pregnancy. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is an inflammatory skin disease that affects 2%–3% of the population worldwide. One of the major challenges in discovering novel therapies is the poor translatability of animal models to human disease. Therefore, it is imperative to develop human preclinical models of psoriasis that are amenable to pharmacological intervention. Here, we report a 3‐D reconstituted human epidermis (RHE) culture system treated with cytokines commonly associated with psoriasis (TNFα, IL‐17A and IL‐22) that reproduced some key features of the human disease. The effects on epidermal morphology, gene transcription and cytokine production, which are dysregulated in psoriasis were assessed. Certain morphological features of psoriatic epidermis were evident in cytokine‐stimulated RHEs, including hypogranulosis and parakeratosis. In addition, RHEs responded to a cytokine mix in a dose‐dependent manner by expressing genes and proteins associated with impaired keratinocyte differentiation (keratin 10/K10, loricrin), innate immune responses (S100A7, DEFB4, elafin) and inflammation (IL‐1α, IL‐6, IL‐8, IL‐10, IL‐12/23p40, IL‐36γ, GM‐CSF and IFNγ) typical of psoriasis. These disease‐relevant changes in morphology, gene transcription and cytokine production were robustly attenuated by pharmacologically blocking TNFα/IL‐17A‐induced NF‐κB activation with IKK‐2 inhibitor IV. Conversely, inhibition of IL‐22‐induced JAK1 signalling with ABT‐317 strongly attenuated morphological features of the disease but had no effect on NFκB‐dependent cytokine production, suggesting distinct mechanisms of action by the cytokines driving psoriasis. These data support the use of cytokine‐induced RHE models for identifying and targeting keratinocyte signalling pathways important for disease progression and may provide translational insights into novel keratinocyte mechanisms for novel psoriasis therapies. [ABSTRACT FROM AUTHOR]

Cytokines IL-17 and IL-22 play pivotal roles in host defense against microbes and in the development of chronic inflammatory diseases. These cytokines are produced by cells that are often located in epithelial barriers, including subsets of T cells and innate lymphoid cells. In general, IL-17 and IL-22 can be characterized as important cytokines in the rapid response to infectious agents, both by recruiting neutrophils and by inducing the production of antimicrobial peptides. Although each cytokine induces an innate immune response in epithelial cells, their functional spectra are generally distinct: IL-17 mainly induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is largely protective and regenerative. In this review, we compare IL-17 and IL-22, describing overlaps and differences in their cellular sources as well as their regulation, signaling, biological functions and roles during disease, with a focus on the contribution of these cytokines to the gut mucosal barrier during bacterial infection.

Atopic dermatitis is one of the most common chronic inflammatory skin diseases caused by both terminal defects in keratinocyte differentiation, and pronounced type 2 immune responses. Atopic dermatitis is a fairly heterogenous disease, depending on the age subtype caused by activation of the Th22, Th17/IL-23 and Th1 cytokine pathway. Clinical studies using classical and targeted therapies have helped to determine contribution of various immune axes to the disease phenotype.We present the modern activation theory mediated by Th2 reactions, due to congenital lymphoid cells of the 2nd group. Correlations between immune response in acute (IL-4, IL-5, IL-13, IL-31, CCL18, IL-22, S100A proteins) and chronic (IFNγ, CXCL9, and CXCL10) manifestations of atopic dermatitis are described. The theory of relationship between clinical manifestations and overexpression of some cytokines (IL-4, IL-13) is discussed. The correlation was shown between peripheral blood phenotype in atopic dermatitis of early childhood and in adult patients and individual production of serum biomarkers. In addition to excess Th17 production, early onset of atopic dermatitis in children correlated with elevated levels of antimicrobial peptides, which may serve as a signaling marker that triggers the disease. The article provides information about relationship between atopic dermatitis and other systemic non-allergic processes and diseases (psoriasis, atherosclerosis, cardiovascular diseases, obesity). Despite different polarity of T cells in atopic dermatitis and psoriasis, and different groups of cytokines produced in these diseases. Psoriasis is most of all due to Th17 associated with activation of IL-17, whereas atopic dermatitis is a consequence of Th2 dominance and associated excessive production of IL-4 and IL-13. The both diseases show activation of Th1 and Th22 with increased production of interferon-γ and IL-22, respectively. The article also concerns an interesting hypothesis on effects of the TWEAK protein upon clinical course of atopic dermatitis and psoriasis. In response to increased TWEAK activity, keratinocytes and skin fibroblasts produce a number of chemoattractant and pro-inflammatory factors commonly found in atopic dermatitis and psoriasis, in particular IL-13 and IL-17. TWEAK is not a single etiological factor for atopic dermatitis or psoriasis, but it causes the production of chemokines that promote chemotaxis of pathogenic inflammatory cells into the skin. With further studies of this pathogenetic factor, it will be possible to synthesize a new targeted drug for the treatment of atopic dermatitis and psoriasis.

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as a-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates a(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut22 Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut22 Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the a-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of a-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. When cancer patients are diagnosed with metastasis, meaning that the primary tumor has spread to at least one different site, their life expectancy decreases dramatically. In the past decade, the immune system´s role in fighting cancer and metastasis has been studied extensively. Importantly, immune cells and inflammatory reactions generate potent antitumor responses but also contribute to tumor development. However, the molecular and cellular mechanisms underlying this dichotomic interaction between the immune system and cancer are still poorly understood. Recently, a spotlight has been cast on the distinct subsets of immune cells and their derived cytokines since evidence has implicated their crucial impact on cancer development. T helper 17 cell (TH17) cells, which express the master transcriptional factor Retinoic acid‐receptor‐related orphan receptor gamma t, are among these critical cell subsets and are defined by their production of type 3 cytokines, such as IL‐17A, IL‐17F, and IL‐22. Depending on the tumor microenvironment, these cytokines can also be produced by other immune cell sources, such as T cytotoxic 17 cell, innate lymphoid cells, NKT cells, or γδ T cells. To date, a lot of data have been collected describing the divergent functions of IL‐17A, IL‐17F, and IL‐22 in malignancies. In this comprehensive review, we discuss the role of these TH17‐ and non‐TH17‐derived type 3 cytokines in different tumor entities. Furthermore, we will provide a structured insight into the strict regulation and subsequent downstream mechanisms of these cytokines in cancer and metastasis. [ABSTRACT FROM AUTHOR]

Cytokines are powerful mediators of inflammation. Consequently, their potency is regulated in many ways to protect the host. Several cytokines, including IL-22, have coordinating binding proteins or soluble receptors that bind to the cytokine, block the interaction with the cellular receptor, and thus prevent cellular signaling. IL-22 is a critical cytokine in the modulation of tissue responses during inflammation and is highly upregulated in many chronic inflammatory disease patients, including those with psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). In healthy individuals, low levels of IL-22 are secreted by immune cells, mainly in the gastrointestinal (GI) tract. However, much of this IL-22 is likely not biologically active due to the high levels of IL-22 binding protein (IL-22BP) produced by intestinal dendritic cells (DCs). IL-22BP is a soluble receptor homolog that binds to IL-22 with greater affinity than the membrane spanning receptor. Much is known regarding the regulation and function of IL-22 in health and disease. However, less is known about IL-22BP. In this review, we will focus on IL-22BP, including its regulation, role in IL-22 biology and inflammation, and promise as a therapeutic. IL-22 can be protective or pathogenic, depending on the context of inflammation. IL-22BP also has divergent roles. Ongoing and forthcoming studies will expand our knowledge of IL-22BP and IL-22 biology, and suggest that IL-22BP holds promise as a way to regulate IL-22 biology in patients with chronic inflammatory disease. [ABSTRACT FROM AUTHOR]

Profound alterations characterize the adaptive immune response in systemic sclerosis, and several layers of evidence support a prominent role exerted by immune cellular effectors and humoral mediators in the pathogenesis of this disease. These include (i) the presence of oligoclonal T cells in tissues undergoing fibrosis consistent with (auto)antigen-specific recruitment, (ii) the preferential expansion of polarized CD4+ and CD8+ T cells producing pro-fibrotic cytokines such as IL-4 and IL-13, (iii) the presence of increased number of cells producing mediators belonging to the IL-17 family, including IL-22, which may drive and participate in inflammatory pathways involving epithelial cells as well as fibroblasts, (iv) the deficient or redirected function of T regulatory cells favoring fibrosis, and (v) the enhanced expression of CD19 and CD21 on naïve B cells, and the upregulation of co-stimulatory molecules in mature B cells, which together with the increased levels of B cell activating factor (BAFF) underlie the propensity to an exaggerated humoral response possibly favoring fibrogenesis. Despite all the progress made in understanding the features of the aberrant immune response in scleroderma, it remains unclear whether the activation of immune effector pathways ultimately drives the disease pathogenesis or rather represents a defective attempt to limit or even reverse excessive extracellular matrix deposition and progressive vasculopathy, the main hallmarks of this disease.

Liver fibrosis occurs in response to any etiology of chronic liver injury including hepatitis B and C, alcohol consumption, fatty liver disease, cholestasis, and autoimmune hepatitis. Hepatic stellate cells (HSCs) are the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in the liver. Various inflammatory and fibrogenic pathways contribute to the activation of HSCs. Recent studies also discovered that liver fibrosis is reversible and activated HSCs can revert to quiescent HSCs when causative agents are removed. Although the basic research for liver fibrosis has progressed remarkably, sensitive and specific biomarkers as non-invasive diagnostic tools, and effective anti-fibrotic agents have not been developed yet. This review highlights the recent advances in cellular and molecular mechanisms of liver fibrosis, especially focusing on origin of myofibroblasts, inflammatory signaling, autophagy, cellular senescence, HSC inactivation, angiogenesis, and reversibility of liver fibrosis.

Cytokines are powerful mediators of inflammation. Consequently, their potency is regulated in many ways to protect the host. Several cytokines, including IL-22, have coordinating binding proteins or soluble receptors that bind to the cytokine, block the interaction with the cellular receptor, and thus prevent cellular signaling. IL-22 is a critical cytokine in the modulation of tissue responses during inflammation and is highly upregulated in many chronic inflammatory disease patients, including those with psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). In healthy individuals, low levels of IL-22 are secreted by immune cells, mainly in the gastrointestinal (GI) tract. However, much of this IL-22 is likely not biologically active due to the high levels of IL-22 binding protein (IL-22BP) produced by intestinal dendritic cells (DCs). IL-22BP is a soluble receptor homolog that binds to IL-22 with greater affinity than the membrane spanning receptor. Much is known regarding the regulation and function of IL-22 in health and disease. However, less is known about IL-22BP. In this review, we will focus on IL-22BP, including its regulation, role in IL-22 biology and inflammation, and promise as a therapeutic. IL-22 can be protective or pathogenic, depending on the context of inflammation. IL-22BP also has divergent roles. Ongoing and forthcoming studies will expand our knowledge of IL-22BP and IL-22 biology, and suggest that IL-22BP holds promise as a way to regulate IL-22 biology in patients with chronic inflammatory disease.

Upon antigenic stimulation, naïve CD4+T cells differentiate into different subsets and secrete various cytokines to exert biological effects. Th22 cells, a newly identified CD4+T cell subset,are distinct from the Th1, Th2 and Th17 subsets. Th22 cells secrete certain cytokines such as IL-22, IL-13 and TNF-α, but not others, such as IL-17, IL-4, or interferon-γ (IFN-γ), and they express chemokine receptors CCR4, CCR6 and CCR10. Th22 cells were initially found to play a role in skin inflammatory diseases, but recent studies have demonstrated their involvement in the development of various autoimmune diseases. Here, we review research advances in the origin, characteristics and effector mechanisms of Th22 cells, with an emphasis on the role of Th22 cells and their main effector cytokine IL-22 in the pathogenesis of autoimmune diseases. The findings presented here may facilitate the development of new therapeutic strategies for targeting these diseases. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. Il20 knockout (Il20 −/−) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. Il20 −/− mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20 −/− mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20 , and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease. [Display omitted] • IL-20 exacerbates acute hepatitis and bacterial infection. • IL-20 selectively inhibits IL-6 and LCN2 expression in hepatocytes by promoting IκBζ protein degradation. • IL-20 induces NQO1 expression in hepatocytes, thereby promoting IκBζ degradation. [ABSTRACT FROM AUTHOR]

Objective High levels of IL-22 are present in serum and synovial fluid of patients with RA. As both pro- and anti-inflammatory roles for IL-22 have been described in studies using animal models of RA, its exact function in arthritis remains poorly defined. With this study we aimed to further unravel the mechanism by which IL-22 exerts its effects and to decipher its therapeutic potential by overexpression of IL-22 either locally or systemically during experimental arthritis. Methods CIA was induced in DBA-1 mice by immunization and booster injection with type II collagen (col II). Before arthritis onset, IL-22 was overexpressed either locally by intra-articular injection or systemically by i.v. injection using an adenoviral vector and clinical arthritis was scored for a period of 10 days. Subsequently, joints were isolated for histological analysis of arthritis severity and mRNA and protein expression of various inflammatory mediators was determined in the synovium, spleen and serum. Results Local IL-22 overexpression did not alter arthritis pathology, whereas systemic overexpression of IL-22 potently reduced disease incidence, severity and pathology during CIA. Mice systemically overexpressing IL-22 showed strongly reduced serum cytokine levels of TNF-α and macrophage inflammatory protein 1α that correlated significantly with the enhanced expression of the negative immune regulator SOCS3 in the spleen. Conclusion With this study, we revealed clear anti-inflammatory effects of systemic IL-22 overexpression during CIA. Additionally, we are the first to show that the protective effect of systemic IL-22 during experimental arthritis is likely orchestrated via upregulation of the negative regulator SOCS3. [ABSTRACT FROM AUTHOR]

Changes in serum cytokines after autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis (MS) patients were documented. Thirty‐six consecutive MS patients who had their Expanded Disability Status Scale (EDSS) scored before AHSCT were prospectively enrolled. Cyclophosphamide (Cy) was infused at 200 mg/kg in two administrations given 10 days apart: the first dose for mobilization, the second as the conditioning regimen. Patients were mobilized with 10 µg/kg/day subcutaneous G‐CSF. Serum was collected 14 days before and 14 after AHSCT. IL‐6, IL‐9, IL‐10, IL 17‐A, IL‐21, IL‐22, IL‐23, TNF‐A, CCL2, CCL3, and CCL4 were measured by magnetic bead‐based immunoassay. t Test and Wilcoxon test were used to compare cytokine levels before and after AHSCT. There were 28 women and 8 men with a median age of 46 (15–62) years, median duration of MS was 9.5 (1–32) years, and EDSS score was 5.7 (1.5–8.0). Patients had a decrement of pro‐inflammatory IL‐21 and IL‐22 (p =.003 and p =.028) and an increment of anti‐inflammatory CCL2 and CCL4 (p <.001 and p =.039) after AHSCT. Decrease of IL‐21 and IL‐22 coupled with an increment of CCL2 and CCL4 could reflect the immunomodulatory effect of auto‐HSCT and be an early indicator of its efficacy. [ABSTRACT FROM AUTHOR]

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Abstract 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.

Both rheumatoid arthritis and periodontitis are complex multifactorial disorders, characterized not only by a dysfunction of basic inflammatory and tissue destructive mechanisms, but also by an altered adaptive and innate immune response in individuals. IL-22 plays an important role in inflammation, including chronic inflammatory diseases and infectious diseases. This study aimed to evaluate the serum levels of IL-22 and ACPA in RA patients. The study included 45 rheumatoid arthritis patients and 35 apparently healthy controls. Enzyme-linked immunosorbent assay (ELISA) has been used for estimation the levels of IL-22 and ACPA in serum of two studied groups. The present results revealed that mean serum levels of IL-22 and ACPA were significantly higher in patients than in healthy controls (p

Transforming growth factor-β1 (TGF-β1) is a crucial factor implicated in the development of renal inflammation and tubulointerstitial fibrosis (TIF). The cytokine interleukin 22 (IL-22) was previously reported to involve in the pathogenesis of chronic inflammatory diseases, however recent studies showed that IL-22 could reduced inflammatory responses and tissue damage. In the present study, we aim to investigate the role and mechanisms of IL-22 in renal tubular cells inflammation and fibrosis induced by TGF-β1. HK-2 cells were treated with TGF-β1 in the presence of IL-22 or the Notch pathway inhibitor dibenzazepine (DBZ) for 48 h. Collagen I (Col I), fibronectin (FN), α-smooth muscle actin (α-SMA), vimentin and E-Cadherin were detected by western blot, proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) were evaluated by ELISA. Jagged1, Notch1, NICD1, and Hes1 were also detected by western blot. We found TGF-β1 increased the levels of Col I, FN, α-SMA and vimentin in HK-2 cells compared with control, and decreased E-Cadherin level, however, IL-22 restored their expressions partly. IL-22 reduced overexpression of proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) levels induced by TGF-β1, along with down-regulation of Jagged1, Notch, NICD1 and Hes1. Fibrosis and inflammation in renal tubular cells induced by TGF-β1 could be attenuated by IL-22, and the effects were similar to DBZ treatment. Collectively, our study shows that IL-22 exerts a protective role in renal fibrotic and inflammatory responses induced by TGF-β1 in vitro, which may be through inhibiting Jagged1/Notch1 signaling pathway activation. [ABSTRACT FROM AUTHOR]

Introduction: Th17 cells are critical mediators of pathology in several autoimmune diseases including multiple sclerosis (MS). The aim of this study was to quantify Th17 cells and-associated cytokines in the peripheral blood of relapsing remitting multiple sclerosis patients (RRMS). We also aimed to compare those levels in fingolimod-treated, and untreated patients. Material and Methods: Fifteen fingolimod administered RRMS, 9 untreated-RRMS patients and 6 healthy controls were evaluated. Their peripheral blood mononuclear cells (PBMCs) were isolated and sera separated. IL-17A+, IL-22+ and GM-CSF+ T-cells were quantified via intracellular cytokine staining after stimulation using flouresecein activated cell sorter. Serum cytokine levels from all groups were measured via enzyme-linked immunosorbent assay (ELISA). Results: Fingolimod-treated RRMS patients had reduced number of IL-17A+ (p=0.02), IL-22+ (p=0.05), and GMCSF+ (p=0.003) T cells in their peripheral blood compared to those of untreated RRMS patients. This is consistent with sequestration of lymphocytes in the secondary lymphoid organs after fingolimod use. However, the levels of same cytokines in the serum were statistically not different. Conclusions: Fingolimod treatment reduced circulating IL-17A+, IL-22+ or GM-CSF+ T cells in RRMS patients. [ABSTRACT FROM AUTHOR]

In recent years, the cytokine interleukin (IL)-22 attracted considerable attention due to its important immunoregulatory function in barrier tissues, such as the gut, lung, and skin. Although a regenerative role of IL-22 in renal tubular damage has been demonstrated, the role of IL-22 in the immunopathogenesis of glomerular injury is still unknown. Here, we demonstrate that the IL-22 receptor is expressed in the glomerular compartment of the kidney and that IL-22 expression increases in the renal cortex after induction of glomerular injury in a mouse model for crescentic glomerulonephritis (cGN, nephrotoxic nephritis). We identified γδ T cells and TH17 cells as major sources for IL-22 in the nephritic kidney. However, neither genetic or antibody-mediated deletion of IL-22 nor genetic deficiency in its endogenous inhibitor IL-22Rα2 (IL-22 binding protein) resulted in substantial phenotypic differences in mice with cGN with respect to crescent formation, tubulointerstitial damage, and kidney function impairment. Similarly, we did not observe significant differences between wild-type or IL-22-deficient mice in a mouse model of secondary focal and segmental glomerulosclerosis (adriamycin-induced nephropathy). As shown previously, we detected concomitant upregulation of IL-17A and IFN-γ production by T cells during the course of cGN, providing alternative cytokine pathways that mediate glomerular injury in this model. In conclusion, we show here that endogenous IL-22 expression is redundant in different forms of glomerular injury, indicating that the IL-22-directed therapies that are being tested in various human diseases might not affect the kidney in patients with glomerular disease. [ABSTRACT FROM AUTHOR]

CD4+ T helper (Th) cells are important regulators of cellular immune response. Newly discovered interleukin (IL)-17-producing CD4+ T cells are known as T helper 17 cells (Th17). They are distinct subset from the T helper type 1 (Th1) and 2 (Th2) lineages. The differentiation of Th17 cells has been intensively studied; however, the role of Th17 cells in different diseases including cancer is still under investigation. Besides IL-17 family cytokines, Th17 cells produce IL-22, IL-21, and IL-26. The dysregulated function of Th17 cells and their cytokines could contribute to pathology of diseases, including cancer. The role of cytokines of Th17 cells such as IL-17, IL-21, and IL-22 in cancer will be discussed in this review. [ABSTRACT FROM AUTHOR]

Background IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. Objective We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. Methods We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti–IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. Results Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10−5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10−19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22–high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22–high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22–low groups. Significant downregulations of multiple immune pathways, including T H 1/ CXCL9 , T H 2/ CCL18 / CCL22 , T H 17/ CCL20 / DEFB4A , and T H 22/ IL22 / S100A's , were restricted to the IL-22–high drug group (P <.05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. Conclusions This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD. [ABSTRACT FROM AUTHOR]

Cytokines are important contributors to immune responses against microbial and environmental threats and are of particular importance at epithelial barriers. These interfaces are continuously exposed to external factors and thus require immune components to both protect the host from pathogen invasion and to regulate overt inflammation. Recently, substantial efforts have been devoted to understanding how cytokines act on certain cells at barrier sites, and why the dysregulation of immune responses may lead to pathogenesis. In particular, the cytokine IL-22 is involved in preserving an intact epithelium, maintaining a balanced microbiota and a functioning defense system against external threats. However, a tight regulation of IL-22 is generally needed, since uncontrolled IL-22 production can lead to the progression of autoimmunity and cancer. Our aim in this review is to summarize novel findings on IL-22 and its interactions with specific microbial stimuli, and subsequently, to understand their contributions to the function of IL-22 and the clinical outcome. We particularly focus on understanding the detrimental effects of dysregulated control of IL-22 in certain disease contexts.

Multiple sclerosis (MS), is a chronic inflammatory disease of central nervous system with unclear etiology. Relapsing-remitting (RR)-MS is the most frequent subtype of disease. Natural Killer (NK) cells have roles in cytotoxicity and immune regulation by cytokine secretions, with uncertain contribution to MS pathogenesis. This study aimed to explore contribution of NK cells to MS pathogenesis. Percentages of CD3 − CD16 + CD56 + total NK cells, CD3 − CD16 + CD56 dim and CD3 − CD16 − CD56 bright NK cell subsets, NK cytotoxicity and intracellular IFN-γ, IL-10 and IL-22 levels were investigated in patients with RR-MS and clinically isolated syndrome (CIS) as well as healthy subjects. Decreased IFN-γ and increased IL-22 production might have detrimental effects on the clinical course of RR-MS. Impaired cytotoxicity is correlated with disease duration in RR-MS. These findings support the possible contribution of NK cells to RR-MS immuno-pathogenesis. [ABSTRACT FROM AUTHOR]