Search

Inflammatory cytokines, interleukin-36 (IL-36), IL-37, IL-38 belong to IL-1 family. The IL-36 subfamily obtains pro- and anti-inflammatory effects on various immune responses. Cytokine IL-37, has anti-inflammatory functions in immunity, and the recently identified IL-38 negatively associated with disease pathogenesis. To date, expression of IL-36, IL-37, IL-38 is reported dysregulated in osteoarthritis (OA) and rheumatoid arthritis (RA), and may be disease markers for arthritis-related diseases. Interestingly, expression of IL-38 was different either in OA patients or animal models, and expression of IL-36Ra in synovium was different in OA and RA patients. Moreover, functional studies have demonstrated significant role of these cytokines in OA and RA progress. These processes were related to immune cells and non-immune cells, where the cytokines IL-36, IL-37, IL-38 may regulate downstream signalings in the cells, and then involve in OA, RA development. In this review, we comprehensively discuss recent advancements in cytokines and the development of OA, RA. We hope that targeting these cytokines will become a potential treatment option for OA and RA in the future. [ABSTRACT FROM AUTHOR]

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients' quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP. [ABSTRACT FROM AUTHOR]

IL-36 cytokines are emerging as beneficial in immunity against pathogens and cancers but can also be detrimental when dysregulated in autoimmune and autoinflammatory conditions. Interest in targeting IL-36 activity for therapeutic purposes is rapidly growing, yet many unknowns about the functions of these cytokines remain. Thus, the availability of robust research tools is essential for both fundamental basic science and pre-clinical studies to fully access outcomes of any manipulation of the system. For this purpose, a floxed Il1rl2, the gene encoding the IL-36 receptor, mouse strain was developed to facilitate the generation of conditional knockout mice. The targeted locus was engineered to contain an inverted mCherry reporter sequence that upon Cre-mediated recombination will be flipped and expressed under the control of the endogenous Il1rl2 promoter. This feature can be used to confirm knockout in individual cells but also as a reporter to determine which cells express the IL-36 receptor IL-1RL2. The locus was confirmed to function as intended and further used to demonstrate the expression of IL-1RL2 in barrier tissues. Il1rl2 expression was detected in leukocytes in all barrier tissues. Interestingly, strong expression was observed in epithelial cells at locations in direct contact with the environment such as the skin, oral mucosa, the esophagus, and the upper airways, but almost absent from epithelial cells at more inward facing sites, including lung alveoli, the small intestine, and the colon. These findings suggest specialized functions of IL-1RL2 in outward facing epithelial tissues and cells. The generated mouse model should prove valuable in defining such functions and may also facilitate basic and translational research. [ABSTRACT FROM AUTHOR]

Background: Sepsis is defined as a life-threatening syndrome caused by an unbalanced host response to infection. The role of interleukin (IL)-36 cytokines binding to the IL-36 receptor (IL-36R) in host response during sepsis remains unknown. Methods: Serum IL-36 level was measured in 47 septic patients sampled on the day of intensive care unit (ICU) and emergency department admission, 21 non-septic ICU patient controls, and 21 healthy volunteers. In addition, the effects of IL-36R deletion on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis was determined. Results: On the day of ICU and emergency department admission, the patients with sepsis showed a significant increase in serum IL-36 levels compared with ICU patient controls and healthy volunteers, and the serum IL-36 levels were related to the severity of sepsis. Non-survivors of septic patients displayed significantly lower serum IL-36 levels compared with survivors. A high serum IL-36 level in ICU and emergency department admission was associated with 28-day mortality, and IL-36 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, IL-36R deletion increased lethality in CLP-induced polymicrobial sepsis. Septic mice with IL-36R deletion had higher bacterial load and demonstrated more severe multiple organ injury (including lung, liver, and kidney) as indicated by clinical chemistry and histopathology. Mechanistically, IL-36R ligands released upon lung damage activated IL-36R+lung fibroblasts thereby inducing expression of the antimicrobial protein lipocalin 2. Moreover, they induced the apoptosis of lung epithelial cells. Conclusions: Septic patients had elevated serum IL-36 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-36R deletion in increasing lethality. [ABSTRACT FROM AUTHOR]

Tissue-specific mechanisms regulate neutrophil immunity at the oral barrier, which plays a key role in periodontitis. Although it has been proposed that fibroblasts emit a powerful neutrophil chemotactic signal, how this chemotactic signal is driven has not been clear. The objective of this study was to investigate the site-specific regulatory mechanisms by which fibroblasts drive powerful neutrophil chemotactic signals within the oral barrier, with particular emphasis on the role of the IL-36 family. The present study found that IL-36γ, agonist of IL-36R, could promote neutrophil chemotaxis via fibroblast. Single-cell RNA sequencing data disclosed that IL36G is primarily expressed in human and mouse gingival epithelial cells and mouse neutrophils. Notably, there was a substantial increase in IL-36γ levels during periodontitis. In vitro experiments demonstrated that IL-36γ specifically activates gingival fibroblasts, leading to chemotaxis of neutrophils. In vivo experiments revealed that IL-36Ra inhibited the infiltration of neutrophils and bone resorption, while IL-36γ promoted their progression in the ligature-induced periodontitis mouse model. In summary, these data elucidate the function of the site-enriched IL-36γ in regulating neutrophil immunity and bone resorption at the oral barrier. These findings provide new insights into the tissue-specific pathophysiology of periodontitis and offer a promising avenue for prevention and treatment through targeted intervention of the IL-36 family. [ABSTRACT FROM AUTHOR]

Aim: There is no marker that can predict whether there is resistance to treatment in patients with psoriasis. In this study, we investigated the relationship between the staining rates of TNF-α, IL-1, IL-12, IL-17, IL-23, and IL-36 markers immunohistochemically from cutaneous biopsy and the treatment success. Methods: The patients who were followed up in the dermatology clinic with the diagnosis of plaque-type psoriasis vulgaris and received biological treatment and previously had cutaneous biopsy were included in the study. The cutaneous biopsies of the cases that met the conditions were re-sectioned and subjected to immunohistochemical examination for TNF-α, IL-1, IL-12, IL-17, IL-23, and IL-36. Results: Comparing the staining scores with psoriasis area severity index (PASI); A statistically significant positive correlation was found between PASI and TNF-α staining score (p = 0.034). A statistically significant positive correlation was found between PASI and IL-17 staining score (p = 0.004). When the staining scores and PASI response rates of psoriasis treatment were evaluated in terms of correlation; there was a positive correlation between TNF-α, IL-17, and IL-23 immunohistochemical staining rates and PASI response rates. Conclusions: In line with the data obtained from our study, we think that making immunohistochemical scoring before the biological treatment decision in psoriasis patients will be beneficial in treatment selection. In this respect, our study may open a new era in the selection of biological treatments for psoriasis. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is an inflammatory skin disease driven by upregulation of cytokines in the Th17 pathway, including interleukin‐36 (IL‐36). Previous studies have highlighted the utility of IL‐36 immunostaining for psoriasis compared to spongiotic dermatitis and other psoriasiform dermatoses; however, no study has examined the role of IL‐36 staining in distinguishing psoriasis from pityriasis rosea (PR) and pityriasis lichenoides (PL), known histologic mimickers of psoriasis. Methods: We compared the immunostaining pattern of IL‐36 for 21 PR cases, 22 PL cases, and 10 psoriasis cases. We graded the immunostaining as 0, negative; 1, focal weak; 2, diffuse weak; 3, focal, strong; or 4, diffuse strong. We further categorized stains as negative (0–2 score) or positive (3–4 score) and utilized Fisher's exact test to compare the immunostaining pattern of these entities. Results: All psoriasis specimens were positive for IL‐36, whereas all PR specimens were negative (p = 0.00000002). Twenty PL specimens were negative (p = 0.000001). Nine of 10 pityriasis lichenoides et varioliformis acuta cases were negative (p = 0.00012), and 11 of 12 cases of pityriasis lichenoides chronica were negative (p = 0.00003). Conclusions: Our findings highlight the potential role of IL‐36 immunostaining in distinguishing psoriasis from other psoriasiform dermatoses, including PR and PL. [ABSTRACT FROM AUTHOR]

The pathogenesis of the inflammatory, chronic, and common skin disease psoriasis involves immune cells, skin cells (keratinocytes), and the cytokines they secrete. Hyperproliferation and abnormal differentiation of keratinocytes are hallmarks of the disease. The roles of cytokines such as TNFa, IL-15, IL-17, and IL-23 in psoriasis have been studied through mathematical/computational models as well as experiments. However, the role of proinflammatory cytokine IL-36 in the onset and progression of psoriasis is still elusive. To explore the role of IL-36, we construct a network embodying indirect cell-cell interactions of a few immune and skin cells mediated by IL-36 based on existing knowledge. We also develop a mathematical model for the network and perform a global sensitivity analysis. Our results suggest that the model is most sensitive to a parameter that represents the level of cytokine IL-36. In addition, a steady-state analysis of the model suggests that an increase in the level of IL-36 could lead to the hyperproliferation of keratinocytes and, thus, psoriasis. Our analysis also highlights that the plaque formation and progression of psoriasis could occur through either a gradual or a switch-like increase in the keratinocyte population. We propose that the switch-like increase would be due to a bistable behavior of the network toward either a psoriatic or healthy state and could be used as a novel treatment strategy. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin disorder characterized by epidermal keratinocyte hyperproliferation and inflammatory infiltration. CCN1 (also termed CYR61 or cysteine‐rich angiogenic inducer 61) is an extracellular matrix‐associated protein that is involved in multiple physiological functions. In psoriasis, we recently demonstrated that the overexpression of CCN1 promoted keratinocyte proliferation and activation. Furthermore, CCN1 was highly expressed in psoriatic skin lesions from psoriasis vulgaris patients. Here, we dissect the underlying molecular mechanism in imiquimod (IMQ) and interleukin (IL)‐23‐induced psoriasis‐like models. Our results demonstrate that CCN1 can significantly upregulate IL‐36 production in the murine skin of IMQ and IL‐23‐induced psoriasis‐like models. Injection of CCN1‐neutralizing antibody improved epidermal acanthosis and significantly reduced IL‐36 production in vivo. These results suggest that CCN1 can be a critical upstream pro‐inflammatory factor in psoriasis. In primary normal human epidermal keratinocytes, we demonstrated that CCN1 can selectively induced the production of IL‐36α and IL‐36γ through the activation of the protein kinase B (AKT)/nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) and extracellular‐regulated kinase (ERK)/CCAAT/enhancer binding protein β (CEBPβ) signaling pathways via integrin receptor α6β1 in vitro. Our results suggest that targeting CCN1 can be a potential therapeutic strategy for psoriasis. [ABSTRACT FROM AUTHOR]

Introduction: Atherosclerosis is a chronic inflammatory process maintained during all stages of the disease by several proinflammatory mediators, such as cytokines and chemokines. Interleukin (IL)-36 cytokines are proinflammatory and have an essential role in innate and adaptive immunity, but the role of IL-36 has not been determined in coronary artery disease (CAD). This study aimed to measure the serum levels of IL-36 in patients with CAD and their association with the serum levels of tumor necrosis factor (TNF)-α, IL-6, and IL-32 and also investigate their correlation with the serum levels of malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP). Methods: A total of 168 subjects (84 CAD and 84 control subjects) were examined in this research. The total serum levels of IL-36 were measured using the enzyme-linked immunosorbent assay (ELISA). Also, some oxidative stress parameters were evaluated by FRAP and MDA assays in the serum. Results: The serum levels of IL-36 and MDA were significantly higher, and FRAP was significantly lower in the CAD group compared to the controls. Furthermore, the serum levels of IL-36, MDA, and FRAP significantly correlated with the CAD group's cardiac arterial stenosis. Also, the serum levels of IL-36 had a positive and significant correlation with the serum levels of TNF-α, IL-6, IL-32, and biochemical parameters in the CAD group. Conclusion: Higher serum levels of IL-36 and its association with the serum levels of TNF-α, IL-32, and IL-6 may play a key role in the pathogenesis of CAD, leading to an increased risk of clogged arteries and oxidative stress. [ABSTRACT FROM AUTHOR]

Netherton syndrome (NS) is a rare autosomal recessive disorder that occurs due to a loss-of-function mutation in SPINK5; this loss results in significant inflammation, as well as perturbations of the skin barrier's integrity and functionality. While it is unclear which inflammatory pathways contribute to the development of NS, recent studies have demonstrated the expression of interleukin (IL)-17/IL-36, as well as several Th2 cytokines. Consequently, immunohistochemistry (IHC) with IL-36 may serve as a potential tool for aiding the histopathological diagnosis of this condition. In this case series, we present two cases of NS and capture their immunostaining pattern with IL-36. Both cases demonstrated robust expression of IL-36. This finding bolsters the hypothesis that NS is partially driven by Th17 activation and suggests the potential utility of IL-36 IHC as part of the workup for this rare and diagnostically elusive entity. LEKTI IHC was negative in one biopsy, revealing a limitation of this stain in diagnosing NS. [ABSTRACT FROM AUTHOR]

The IL-36 family of cytokines were first identified in 2000 based on their sequence homology to IL-1 cytokines. Over subsequent years, the ability of these cytokines to either agonise or antagonise an IL-1R homologue, now known as the IL-36 Receptor (IL-36R), was identified and these cytokines went through several cycles of renaming with the current nomenclature being proposed in 2010. Despite being identified over 20 years ago, it is only during the last decade that the function of these cytokines in health and disease has really begun to be appreciated, with both homeostatic functions in wound healing and response to infection, as well as pathological functions now ascribed. In the disease context, over activation of IL-36 has now been associated with many inflammatory diseases including Psoriasis and inflammatory bowel diseases, with roles in cancer also now being investigated. This review summarises the current knowledge of IL-36 biology, its role in inflammatory diseases and focuses on an emerging role for IL-36 in cancer. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-36 family cytokines have received increasing attention, especially in the fields of inflammation and immunity research. However, whether IL-36 family cytokine levels are correlated with the results of the assessment of allergic rhinitis (AR) and affect the severity of AR remains unknown. Therefore, this study aimed to investigate the correlations between IL-36 family cytokine levels and subjective and objective assessment results and to further analyze the possible mechanisms of IL-36 family cytokines in the development of AR. Methods: An enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of the IL-36 family cytokines IL-36α, IL-36β, IL-36γ, IL-36Ra, and IL-38 in the peripheral blood of patients with AR. The condition of patients with AR was assessed by 22-item sino-nasal outcome test (SNOT-22) score, visual analogue scale (VAS) scores for disease severity, and serum inhalant allergen immunoglobulin E (IgE) detection. Correlations between IL-36 family cytokine levels and subjective and objective assessment results in patients with AR were analyzed. Results: The concentration of IL-36α in the peripheral blood of patients with AR was the highest, and the concentration of IL-36β was the lowest. The concentration of IL-36α was higher in juvenile patients than in adult patients, and there was a difference in the IL-36Ra level between the perennial allergen group and the seasonal allergen group. There was a positive correlation between IL-36α level and IL-36γ level, IL-36γ level and IL-36Ra level, and IL-36Ra level and IL-38 level, and IL-36β level was positively correlated with IL-36Ra and IL-38 levels, respectively. IL-36α level was positively correlated with VAS score for nasal congestion symptom. IL-36β level was positively correlated with the total VAS score for ocular symptoms and VAS scores for ocular itching and eye pain symptoms. However, there was no correlation between the levels of all cytokines in IL-36 family and SNOT-22 score, the number of positive inhaled allergens, or the highest positive intensity of allergen specific immunoglobulin E (sIgE). Conclusion: Peripheral blood IL-36 family cytokines play an important role in AR, and the concentrations of IL-36α and IL-36β were related to the severity of symptoms in patients with AR. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33), IL-36, and IL-38 are members of the IL-1 cytokine family. The expression of each cytokine has been reported to be increased in the inflamed mucosa of patients with inflammatory bowel disease (IBD). IL-33 and IL-36 have been studied for pro- and anti-inflammatory functions, and IL-38 has been characterized as an anti-inflammatory cytokine by antagonizing the IL-36 receptor (IL-36R). IL-33 is a nuclear cytokine constitutively expressed by certain cell types such as epithelial, endothelial, and fibroblast-like cells and released on necrotic cell death. IL-33 mainly induces type 2 immune response through its receptor suppression tumorigenicity 2 (ST2) from Th2 cells and type 2 innate lymphoid cells (ILC2s), but also by stimulating Th1 cells, regulatory T cells, and CD8+ T cells. IL-36 cytokines consist of three agonists: IL-36α, IL-36β, and IL-36γ, and two receptor antagonists: IL-36R antagonist (IL-36Ra) and IL-38. All IL-36 cytokines bind to the IL-36R complex and exert various functions through NF-κB and mitogen-activated protein kinase (MAPK) pathways in inflammatory settings. IL-33 and IL-36 also play a crucial role in intestinal fibrosis characteristic manifestation of CD. In this review, we focused on the current understanding of the pro- and anti-inflammatory roles of IL-33, IL-36, and IL38 in experimental colitis and IBD patients. [ABSTRACT FROM AUTHOR]

A member of the interleukin (IL)-1 superfamily was IL-36, which contained IL-36α, IL-36β, IL-36γ, and IL-36Ra. Heterotrimer complexes, consisting of heterodimeric receptor complexes and IL-36 agonist, gave signals through intracellular functional domains, so as to bind to downstream proteins and induce inflammatory response. IL-36 agonists upregulated mature-associated CD80, CD86, MHCII, and inductively produced several pro-inflammatory cytokines through the IL-36R-dependent manner in dendritic cells (DCs). Besides, DCs had the ability to initiate the differentiation of helper T (Th) cells. Up to date, the role of IL-36 in immunity, inflammation and other diseases is of great importance. Additionally, autoimmune diseases were characterized by excessive immune response, resulting in damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases were related to inflammatory response. In this review, we will conclude the recent research advances of IL-36 in the occurrence and development of autoimmune diseases, which may provide new insight for the future research and the treatment of these diseases. [ABSTRACT FROM AUTHOR]

IL-36 cytokines are members of the IL-1 superfamily. Increasing evidence in the IL-36 pathway demonstrates their potential as a therapeutic target for treating inflammatory skin diseases, such as generalized pustular psoriasis (GPP). A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses. IL-36 has important downstream effects such as inducing expression of inflammatory cytokines, antimicrobial peptides, and growth factors. Increased expression of IL-36 cytokines has been observed in the lesional skin of patients with psoriasis. Studies of other inflammatory skin diseases have also noted similar findings, albeit to a lesser extent. IL-36 inhibition has been shown to be effective in GPP and is currently being studied for other inflammatory skin diseases. The IL-36 pathway contributes to pathogenesis of many inflammatory skin diseases and is a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Acne vulgaris (AV) is an extraordinarily common skin condition. The high prevalence of AV is linked to the exposure factors, as environmental pollutants and climatic factors, occupational, psychosocial, and lifestyle factors. The AhR plays a critical part in environmental toxic action. The AhR expression and imbalance in the IL‐36 & 38 expression may have a role in inflammation and AV pathogenesis. Aims: To detect possible links between environmental, inflammatory, and anti‐inflammatory factors in AV pathogenesis through measuring AhR, IL‐36, and IL‐38 mRNA gene expression levels. Patients and Methods: Total of 100 subjects (70 AV patients and 30 apparently healthy control subjects) were tested for AhR, IL‐36γ, and IL‐38 mRNA levels by quantitative real‐time PCR. Results: The median levels of AhR and IL‐36 mRNA gene expression were considerably greater, while that of IL‐38 was essentially lower in AV than healthy subjects (p < 0.001, 0.021 and 0.002, respectively). The AhR and IL‐36 mRNA gene expression levels increased, while IL‐38 decreased significantly with higher grades of severity (p < 0.001, 0.001, and <0.001, respectively). ROC curve showed that AhR mRNA gene expression level had the best AUC for diagnosis of AV, with better sensitivity and specificity than IL‐36 and IL‐38. Conclusions: Higher levels of AhR, IL‐36, and lower levels of IL‐38 gene expression were significantly associated with AV patients and higher grades of severity. AhR had better diagnostic ability than IL‐38 and IL‐36. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is an autoimmune bullous disease, characterized by autoantibodies targeting BP180 and BP230. The role of interleukin (IL)‐36, a potent chemoattractant for granulocytes, in BP remains elusive.The expression of IL‐36 cytokines (IL‐36α, β, γ) and their antagonists (IL‐36Ra and IL‐38) was analysed in the skin and serum samples of patients with BP (n = 31), psoriasis (n = 10) and healthy controls (HC) (n = 14) by quantitative polymerase chain reaction and enzyme linked immunosorbent assay, respectively. Skin and serum levels of all cytokines were correlated with the Bullous Pemphigoid Disease Area Index (BPDAI) score and with the serum concentration of pathogenic antibodies.IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra were significantly (p < 0.05) overexpressed in BP skin compared to HC, without remarkable differences relative to psoriasis skin. The expression of IL‐38 was significantly (p < 0.05) higher in BP compared to psoriasis skin.IL‐36α and γ, but not β, serum concentrations were significantly (p < 0.05) higher in BP compared to HC. IL‐36γ was significantly (p < 0.05) more expressed in the serum of psoriasis patients than BP. The serum concentration of IL‐36Ra and IL‐38 were similar between BP and HC, while IL‐38 serum levels were significantly (p < 0.05) higher in BP compared to psoriasis patients. Serum IL‐36α correlated significantly with BPDAI (r = 0.5 p = 0.001).IL‐36 agonists are increased in BP patients, both locally and systemically. Serum IL‐36α might represent a potential biomarker for BP. An inefficient balance between IL‐36 agonists and antagonists is likely to occur during BP inflammation. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare yet severe variant of psoriasis, characterized by the eruption of superficial sterile pustules that appear suddenly and widely distributed, potentially life-threatening. It more commonly presents through recurrent acute flares triggered by stress, corticosteroid withdrawals, pregnancy, or infections. The pathogenesis of this disease is yet to be fully understood. Nevertheless, studies have suggested an important role of an IL-1 subfamily of cytokines, due to an imbalance of the IL-36 axis favoring of pro-inflammatory activity. The therapeutic intervention for this condition is still a challenge as its rarity and scarce available information contribute to the absence of specific treatment. Current options stand on small, open-label trials or follows standard treatment for plaque psoriasis. Spesolimab and imsidolimab are two IL-36 receptor inhibitors which completed phase 1 and 2 trials with a good efficacy and safety profile in the treatment of this disease, including in the fast control of its acute flares. The most common adverse events reported with spesolimab were mild to moderate infections, and imsidolimab was well tolerated. GPP clinical trials remain to have their small sample size as a major limitation, but IL-36 receptor inhibitors are promising therapeutic options currently under investigation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has garnered considerable attention due to its morbidity and mortality. Although the precise mechanisms underlying HCC tumorigenesis remain to be elucidated, evidence suggests that host immunity plays a pivotal role in its development. IL-36 and IL-37 are important immunoregulatory cytokines classified as pro-inflammatory and anti-inflammatory respectively. In the context of HCC, the downregulation of intrahepatic IL-36 is inversely correlated with cirrhosis, but positively correlated with 5-year survival rates, suggesting that IL-36 offers protection during HCC development. However, IL-36 may lose its hepatoprotective effects as the disease progresses to HCC in the context of dysregulated immunity in cirrhotic patients. Substantially increased circulating IL-36 in HCC patients is likely a systemic response to HCC stimulation, but is insufficient to suppress progression towards HCC. Intrahepatic IL-37 is suppressed in HCC patients, consistent with the inverse correlation between intrahepatic IL-37 and the level of AFP in HCC patients, suggesting IL-37 exerts hepatoprotection. There is no significant difference in IL-37 among differentiations of HCC or with respect to clinical BCLC stages or cirrhosis status in HCC patients. However, IL-37 protection is demonstrated in an IL-37 transfected HCC animal model, showing significantly reduced tumour size. IL-36/37 may inhibit HCC by enhancing M1 tumour-associated macrophages while not affecting M2 macrophages. The interplay between IL-36 (pro-inflammatory) and IL-37 (anti-inflammatory) is emerging as a crucial factor in host protection against the development of HCC. Further research is needed to investigate the complex mechanisms involved and the therapeutic potential of targeting these cytokines in HCC management. [ABSTRACT FROM AUTHOR]

Crimean–Congo hemorrhagic fever (CCHF) is a severe viral disease. The scientific literature is growing, emphasizing the significance of the interleukin (IL)‐36 family in the proinflammatory signaling pathway. However, to date, no research has explored the potential of IL‐36 family members as biomarkers in CCHF. This study aims to bridge this gap by evaluating IL‐36α, IL‐36β, and IL‐36γ levels in CCHF patients and healthy controls and investigating their association with disease severity and prognosis. Sixty confirmed CCHF patients and 29 healthy controls were enrolled in this case‐control study. Serum levels of IL‐36α, IL‐36β, and IL‐36γ were measured using enzyme‐linked immunosorbent assays. Significantly higher levels of IL‐36α and IL‐36β were observed in CCHF patients compared to healthy controls (p < 0.05). However, no statistically significant changes were found in IL‐36γ levels between the two groups. Among the CCHF patients, those who did not survive exhibited significantly elevated IL‐36α and IL‐36γ levels compared to survivors (p < 0.01). Positive correlations were identified between IL‐36α and IL‐36γ levels with activated partial thromboplastin time, and D‐dimer (p < 0.01). Conversely, platelet levels showed a negative correlation with IL‐36α and IL‐36γ levels (p < 0.01). The increased levels of IL‐36α, IL‐36β, and IL‐36γ in patients indicate their participation in proinflammatory reactions in CCHF patients. Understanding the role of IL‐36 family members in CCHF pathogenesis could offer valuable insights into disease progression and facilitate the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 is a member of the IL-1 superfamily and includes three agonists (IL-36α, IL-36β, and IL-36γ) and an antagonist (IL-36Ra). IL-36 agonists bind to heterodimeric receptor complexes. Then, the heterotrimer complexes signal via intracellular functional domains, binding to downstream signaling proteins and inducing inflammatory responses. In this review, we summarized the current knowledge about the biological role of IL-36 and its correlation with systemic inflammatory diseases. The information collected will help to increase the understanding of the potential of IL-36 and may give clues for developing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease’s development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses proinflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities. [ABSTRACT FROM AUTHOR]

Fibrosis is an abnormal repair process of the organism activated by tissue injury, with the typical pathological manifestation of excessive deposition of extracellular matrix, ultimately leading to the destruction of normal tissue structure as well as organ hypofunction or even failure. The development of targeted anti-fibrotic drugs has been hampered by the fact that the specific mechanism is not yet clear. There is growing evidence that interleukin-36 （IL-36） has an important role in the development of fibrotic diseases. Aberrant expression of IL-36 cytokines is observed in idiopathic pulmonary fibrosis, liver fibrosis, renal interstitial fibrosis, inflammatory bowel disease-associated intestinal fibrosis, and cardiac fibrosis. Inhibition or knockdown of IL-36 can effectively prevent or even reverse fibrotic lesions, and its mechanism is closely related to the regulation of immune cell responses, the activation of fibroblasts, and the regulation of related enzyme activity. In this paper, we review the recent research progress of IL-36 and its expression and pro-fibrotic mechanisms in different fibrotic diseases in order to provide a reference for further research. [ABSTRACT FROM AUTHOR]

Background: Rosacea is a chronic inflammatory skin disease. Previous studies have determined that IL-36, IL-37, and IL-38 may play a role in the pathogenesis of various inflammatory diseases. Aims and Objectives: The present study aims to evaluate the relationship of these cytokines with rosacea. Materials and Methods: A total of 100 individuals, including 50 patients with rosacea and 50 healthy controls, were included in the study. IL-36, IL-37, and IL-38 levels were measured using the ELISA method by taking serum samples from all participants. Results: The mean serum levels of IL-36, IL-37, and IL-38 in the patient group were 52.17 ± 24.07 pg/ml, 18.46 ± 8.18 pg/ml, and 25.74 ± 8.36 ng/l, respectively. The mean serum levels of IL-36, IL-37, and IL-38 in the control group were 32.99 ± 19.90 pg/ml, 44.61 ± 22.27 pg/ml, and 45.61 ± 17.32 ng/l, respectively. The difference between the serum levels of IL-36, IL-37, and IL-38 in the patient and control groups was statistically significant (P < 0.001). Conclusion: Based on these findings, an increase in IL-36 and a decrease in IL-37 and IL-38 may contribute to the pathogenesis of rosacea. Future rosacea treatments could target and/or interact with these possible steps in the pathogenesis of rosacea. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, immune‐mediated skin disease that affects over 3% of adults in the United States. Psoriasis can present in several clinical forms. Of these, generalized pustular psoriasis is an acute, severe form, associated with increased morbidity and mortality. Unlike the more common plaque psoriasis, which is thought to feature dysregulation of the adaptive immune system, generalized pustular psoriasis reflects heightened autoinflammatory responses. Recent advances in genetic and immunological studies highlight a key role of the IL‐36 immune axis in the pathogenesis of generalized pustular psoriasis. In this article, we review the psoriatic subtypes and discuss diagnostic criteria of generalized pustular psoriasis, discuss several newly identified genetic variants associated with pustular disease in the skin, and discuss how these mutations shed light on pustular disease mechanisms. Furthermore, we gather insights from recent transcriptomic studies that similarly implicate a pathogenic role of the IL‐36 immune axis in generalized pustular psoriasis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: IL‐36 might play a role as an initial immune mechanism against chikungunya fever, and regulating IL‐36 production could be a potential treatment approach for this condition. Two Japanese siblings visited Cook Islands in 2015 and developed Chikungunya fever upon their return. The sister experienced high fever, joint pain, and leg swelling, while the brother had joint pain and a rash. Both siblings had a confirmed CHIKV infection and continued to experience prolonged joint pain, with the sister enduring chronic pain for about a year. In this study, the levels of IL‐36 in the serum of two siblings who were infected with chikungunya fever during the acute and recovery phases were compared using ELISA. IL‐36 is a cytokine that induces inflammation and is produced by cells in tissues such as the skin and mucosa. It was hypothesized that IL‐36 may be involved in persistent joint pain after chikungunya fever infection. Both siblings experienced long‐lasting joint pain after chikungunya fever infection. The levels of IL‐36α and IL‐36β decreased by 56 days after infection. In the results, IL‐36 plays an important role in host immunity and may act as part of the immune response during chikungunya virus infection. Inhibiting the release of IL‐36 could be a promising approach for developing new treatment methods for chikungunya fever. [ABSTRACT FROM AUTHOR]

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies. [ABSTRACT FROM AUTHOR]

Inflammation driven by environmental allergens is an important source of morbidity in diseases such as asthma and eczema. How common allergens promote inflammation is still poorly understood, but previous studies have implicated the protease activity associated with many allergens as an important component of the pro-inflammatory properties of these agents. The IL-1 family cytokine, IL-33, has recently been shown to undergo processing and activation by proteases associated with multiple common allergens. However, it remains unclear whether the sensing of exogenous protease activity—as a proxy for the detection of invasive microbes, allergens and parasitic worms—is a general property of IL-1 family cytokines. In common with the majority of IL-1 family members, cytokines within the IL-36 sub-family (IL-36α, IL-36β and IL-36γ) are expressed as inactive precursors that require proteolysis within their N-termini for activation. Here we show that proteases associated with multiple common allergens of plant, insect, fungal and bacterial origin (including: Aspergillus fumigatus , ragweed, rye, house dust mite, cockroach and Bacillus licheniformis) are capable of processing and activating IL-36 family cytokines, with IL-36β being particularly susceptible to activation by multiple allergens. Furthermore, extracts from several allergens also processed and enhanced IL-1α activity. This suggests that multiple IL-1 family cytokines may serve as sentinels for exogenous proteases, coupling detection of such activity to unleashing the pro-inflammatory activity of these cytokines. Taken together with previous data on the diversity of proteases capable of activating IL-1 family cytokines, this suggests that members of this cytokine family may function as 'activity recognition receptors' for aberrant protease activity associated with infection, tissue injury or programmed necrosis. [ABSTRACT FROM AUTHOR]

Abstract: The recently discovered interleukin (IL)‐36 family of cytokines form part of the broader IL‐1 family and are emerging as important mediators of inflammatory disease. The IL‐36 subfamily consists of three ligands—IL‐36α, IL‐36β, and IL‐36γ—and the natural antagonist IL‐36Ra. The cytokines exert their effects through a specific IL‐36 receptor consisting of IL‐36R and IL‐1RAcP chains. IL‐36 cytokines can direct both innate and adaptive immune responses by acting on parenchymal, stromal, and specific immune cell subsets. In humans, inactivating mutations in the gene encoding the IL‐36R antagonist, which lead to unregulated IL‐36R signaling, lead to an autoinflammatory condition termed deficiency of the IL‐36R antagonist, which primarily manifests as a severe form of pustular psoriasis. While such discoveries have prompted deeper mechanistic studies highlighting the important role of IL‐36 cytokines in psoriatic skin inflammation, it is now evident that IL‐36 cytokines can also play important roles in inflammatory disorders in other organs, such as the gastrointestinal tract and the lungs. Given these emerging roles, strategies to specifically target the expression and activity of the IL‐36 family have the potential to uncover novel therapeutic approaches aimed at treating inflammatory diseases in humans. [ABSTRACT FROM AUTHOR]

Background: The interleukin (IL)-36 cytokines are a sub-family of the IL-1 family which are becoming increasingly implicated in the pathogenesis of inflammatory diseases and malignancies. Initial studies of IL-36 signalling in tumorigenesis identified an immune-mediated anti-tumorigenic function for these cytokines. However, more recent studies have shown IL-36 cytokines also contribute to the pathogenesis of lung and colorectal cancer (CRC). Methods: The aim of this study was to investigate IL-36 expression in CRC using transcriptomic datasets and software such as several R packages, Cytoscape, GEO2R and AnalyzeR. Validation of results was completed by qRT-PCR on both cell lines and a patient cohort. Cellular proliferation was assessed by flow cytometry and resazurin reduction. Results: We demonstrate that IL-36 gene expression increases with CRC development. Decreased tumoral IL-36 receptor expression was shown to be associated with improved patient outcome. Our differential gene expression analysis revealed a novel role for the IL-36/IL-17/IL-23 axis, with these findings validated using patient-derived samples and cell lines. IL-36γ, together with either IL-17a or IL-22, was able to synergistically induce different genes involved in the IL-17/IL-23 axis in CRC cells and additively induce colon cancer cell proliferation. Conclusions: Collectively, this data support a pro-tumorigenic role for IL-36 signalling in colon cancer, with the IL-17/IL-23 axis influential in IL-36-mediated colon tumorigenesis. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 is a member of the IL-1 superfamily, which includes three receptor agonists and one antagonist and exhibits a familial feature of inflammatory regulation. Distributed among various tissues, such as the skin, lung, gut and joints, the mechanism of IL-36 has been most completely investigated in the skin and has been used in clinical treatment of generalized pustular psoriasis. Meanwhile, the role of IL-36 in the intestine has also been under scrutiny and has been shown to be involved in the regulation of various intestinal diseases. Inflammatory bowel disease and colorectal cancer are the most predominant inflammatory and neoplastic diseases of the intestine, and multiple studies have identified a complex role for IL-36 in both of them. Indeed, inhibiting IL-36 signaling is currently regarded as a promising therapeutic approach. Therefore, the present review briefly describes the composition and expression of IL-36 and focuses on the role of IL-36 in intestinal inflammation and colorectal cancer. The targeted therapies that are currently being developed for the IL-36 receptor are also discussed. [ABSTRACT FROM AUTHOR]

Background: Elevated epidermal interleukin (IL)‐36 expression distinguishes psoriasis from eczematous dermatitis, but other psoriasiform dermatitides (PDs) have not been thoroughly investigated for IL‐36 expression. In this study, we assess the IL‐36 staining pattern (IL36‐SP) in psoriasis variants and other PDs including lichen simplex chronicus (LSC), prurigo nodularis (PN), lichen planus (LP), tinea, pityriasis rubra pilaris (PRP), mycosis fungoides (MF), pemphigus foliaceus (PF), acute generalized exanthematous pustulosis (AGEP), impetigo (IMP), and syphilis (SY). Methods: IL‐36 immunostaining was performed on 307 cases of psoriasis and various PDs. IL36‐SP in the upper epidermis was graded on a scale of 0‐4. Results: High IL36‐SP occurred in all variants of psoriasis, as well as in AGEP, PRP, PN, tinea, IMP, and LP (P > 0.05). SY, PF, LSC, and MF showed a lower IL36‐SP (P ≤ 0.05) compared with psoriasis. Conclusion: All variants of psoriasis exhibit high IL36‐SP. IL‐36 staining can assist in differentiating MF, PF, SY, and LSC from psoriasis, particularly MF and LSC, which have consistent low IL‐36 expression. AGEP, PRP, tinea, IMP, PN, and LP exhibit high IL‐36 expression similar to psoriasis, indicating Th17 activation in these diseases. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)‐36, including IL‐36α, IL‐36β, and IL‐36γ in the IL‐1 family, are agonists of their receptors. IL‐36 expression is associated with inflammation, including lung infection in humans. However, there is no information on its role in the inflammation of different types of chronic obstructive pulmonary disease (COPD). Objective: This study focused on the sputum IL‐36α, IL‐36β, and IL‐36γ levels in stable COPD patients and their relationship with lung function and other cytokines in different inflammatory types of COPD patients. Methods: Sputum specimens were collected from 73 stable COPD patients and 20 age‐ and gender‐matched healthy controls. The levels of sputum IL‐36α, IL‐36β, and IL‐36γ and other cytokines were quantified and sputum cells were characterized. The potential relationship between the levels of sputum IL‐36α, IL‐36β, or IL‐36γ and lung functional measures, inflammatory cells, and cytokines was analyzed. Results: In comparison with the healthy controls, sputum IL‐36α and IL‐36γ levels significantly increased in COPD (106.8 pg/mL vs. 76.9 pg/mL P =.001, 397.9 pg/mL vs. 359.5 pg/mL P =.006). The sputum IL‐36α and IL‐36γ levels were significantly higher in the neutrophilic and mixed granulocytic types than that in the eosinophilic and paucigranulocytic types of COPD patients. The sputum IL‐36α levels were positively correlated with sputum IL‐36γ levels and the numbers of sputum neutrophils, and the sputum IL‐36γ levels were positively correlated with the numbers of sputum lymphocytes in COPD patients. Conclusions: Elevated levels of sputum IL‐36α and IL‐36γ were detected in COPD patients and may provide insights into the inflammatory pathways in neutrophilic COPD. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 cytokines are members of the IL-1 superfamily of cytokines. IL-36 cytokines are composed of three agonists (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36 receptor antagonist [IL36Ra] and IL-38). These work in innate and acquired immunity and are known to contribute to host defense and to the pathogenesis of autoinflammatory diseases, autoimmune diseases, and infectious diseases. In the skin, IL-36α and IL-36γ are mainly expressed by keratinocytes in the epidermis, although they are also produced by dendritic cells, macrophages, endothelial cells, and dermal fibroblasts. IL-36 cytokines participate in the first-line defense of the skin against various exogenous assaults. IL-36 cytokines play significant roles in the host defense system and in the regulation of inflammatory pathways in the skin, collaborating with other cytokines/chemokines and immune-related molecules. Thus, numerous studies have shown IL-36 cytokines to play important roles in the pathogenesis of various skin diseases. In this context, the clinical efficacy and safety profiles of anti-IL-36 agents such as spesolimab and imsidolimab have been evaluated in patients with generalized pustular psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, acne/acneiform eruptions, ichthyoses, and atopic dermatitis. This article comprehensively summarizes the roles played by IL-36 cytokines in the pathogenesis and pathophysiology of various skin diseases and summarizes the current state of research on therapeutic agents that target IL-36 cytokine pathways. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 family is closely associated with inflammation and consists of IL-36α, IL-36β, IL-36γ, and IL-36Ra. The role of IL-36 in the context of asthma and asthmatic phenotypes is not well characterized. We examined the sputum IL-36 levels in patients with different asthma phenotypes in order to unravel the mechanism of IL-36 in different asthma phenotypes. Our objective was to investigate the induced sputum IL-36α, IL-36β, IL-36γ, and IL-36Ra concentrations in patients with mild asthma, and to analyze the relationship of these markers with lung function and other cytokines in patients with different asthma phenotypes. Induced sputum samples were collected from patients with mild controlled asthma (n = 62, 27 males, age 54.77 ± 15.49) and healthy non-asthmatic controls (n = 16, 10 males, age 54.25 ± 14.60). Inflammatory cell counts in sputum were determined. The concentrations of IL-36 and other cytokines in the sputum supernatant were measured by ELISA and Cytometric Bead Array. This is the first study to report the differential expression of different isoforms of IL-36 in different asthma phenotypes. IL-36α and IL-36β concentrations were significantly higher in the asthma group (P = 0.003 and 0.031), while IL-36Ra concentrations were significantly lower (P < 0.001) compared to healthy non-asthmatic controls. Sputum IL-36α and IL-36β concentrations in the neutrophilic asthma group were significantly higher than those in paucigranulocytic asthma (n = 24) and eosinophilic asthma groups (n = 23). IL-36α and IL-36β showed positive correlation with sputum neutrophils and total cell count (R = 0.689, P < 0.01; R = 0.304, P = 0.008; R = 0.689, P < 0.042; R = 0.253, P = 0.026). In conclusion, IL-36α and IL-36β may contribute to asthma airway inflammation by promoting neutrophil recruitment in airways. Our study provides insights into the inflammatory pathways of neutrophilic asthma and identifies potential therapeutic target. [ABSTRACT FROM AUTHOR]

IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B, or IL-36G. We identified some early IL-1Bspecific responses (8 h posttreatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 h posttreatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 h) followed by no response or repression (24 h). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 and 24 h). These involved upregulation of ligands (IL1A, IL1B, and IL36G) and activating proteases (CTSS) but also upregulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, inflammatory bowel disease, and primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses. [ABSTRACT FROM AUTHOR]

Purpose of Review: Since the discovery of its very first member in 1974, the IL-1 family has expanded into a group of 11 potent molecules which are essential in both innate and acquired immunity. Pro-inflammatory cytokines IL-36α, IL-36β, and IL-36γ and their receptor antagonists IL-36Ra and IL-38, which belong to the IL-36 subfamily, are some of the most recently identified members. Recent studies show that these members possess pro-inflammatory and anti-inflammatory activities and may take part in the pathogenesis of allergy. In this review, the involvement and importance of these newly described IL-1 family members in the most common allergic diseases, i.e., atopic dermatitis (AD), allergic asthma, and allergic rhinitis, will be discussed. Recent Findings: Dysregulation of IL-36 and IL-38 was observed in the skin and respiratory tract of AD, allergic rhinitis, and allergic asthma individuals. Although the upregulation in IL-36α and IL-36γ observed in the lesional skin of AD patients was unexpectedly small, IL-36 may play an important role in AD pathogenesis especially upon Staphylococcus aureus colonization. While IL-36γ regulates eosinophils to induce an inflammatory response in allergic rhinitis, IL-36α was found to regulate Th17 immunity. IL-36 receptor antagonists, IL-36Ra and IL-38, however, both show promising anti-inflammatory activities against allergic asthma. Of note, IL-38 in allergic asthmatic children is significantly lower than their healthy counterparts, while the anti-inflammatory effects of IL-38 in allergic asthma exacerbation upon viral-like infection were demonstrated in in vitro, HDM-induced, and humanized mice models. Summary: Dysregulated expression of IL-36 and IL-38 observed in allergic patients and mice models revealed that they may have essential roles in the pathogenesis in AD, allergic rhinitis, and allergic asthma, especially during the host defense against pathogens at inflammatory sites. Their receptor antagonists, IL-36Ra and IL-38, could also be promising biologics in the control of allergy. Since allergic diseases are phenotypically complex, contradictory data obtained in different studies may be explained if further stratification of disease endotypes is explored. Genetically modified mice model and investigation in anti-IL-36 treatment may be useful to characterize the therapeutic potential of these cytokines in the regulation of allergy in the future. [ABSTRACT FROM AUTHOR]

A well-characterised example of a complete self-regulated inflammatory pathway is the interleukin-1 (IL-1) system comprising the agonist cytokines IL-1 and IL-1 , and their receptor IL-1R1 (IL-1 receptor type I), which is inhibited by the IL-1 receptor antagonist IL-1Ra.1 A related system involves the three IL-36 cytokines IL-36 , IL-36 and IL-36 , which are neutralised when the IL-36Ra binds the IL-36 receptor IL-1RL2 (also known as IL-36R). In agreement with this, histological analyses of epidermal and dermal thickness did not reveal statistically significant differences between wild-type and IL-36 -, IL-36 - or IL-36 -deficient mice (Figure 1C-D). Hence, we also evaluated expression levels of a number of cytokines linked to the disease phenotype6 and previously shown to be regulated by IL-36 directly or indirectly.1 Inflammation was clearly induced in all four strains, as chemokines not measurable in normal ears were readily detected after DNFB treatment. [Extracted from the article]

Background: Members of the interleukin (IL)‐36 family, IL‐36α, IL‐36β and IL‐36γ, are potent chemoattractive cytokines for neutrophils and eosinophils. IL‐36 receptor antagonist (IL‐36Ra) inhibits IL‐36α, IL‐36β and IL‐36γ activity. However, the immunohistological expression of IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra has never been addressed in normal follicles, folliculitis or eosinophilic pustular folliculitis (EPF). Methods: We performed immunohistochemical staining for IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra using 10 cases of EPF, nine of non‐specific folliculitis, 10 normal skin samples and 10 samples of normal follicles adjacent to a sebaceous naevus as a control. Two dermatologists, who were blind to the patient records, evaluated all of the slides. Results: The immunoreactive IL‐36α was hardly detected in the follicular epithelium and epidermis in the normal skin, folliculitis or EPF. The expression of IL‐36β, IL‐36γ and IL‐36Ra was augmented in both folliculitis and EPF compared with that in normal follicles. Negative correlations were detected between IL‐36β and IL‐36Ra and between IL‐36γ and IL‐36Ra in normal follicles; however, these were absent in folliculitis. In contrast to normal follicles and folliculitis, a significant positive correlation between IL‐36β/γ and IL‐36Ra was shown in EPF. Conclusions: The overexpression of IL‐36β, IL‐36γ and IL‐36Ra is an integral part of the inflammatory response of folliculitis and EPF. The coordinated expression of IL‐36γ and IL‐36Ra may be related to the pathomechanism of EPF. [ABSTRACT FROM AUTHOR]

Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1β. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S–processed form of this cytokine,was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R−/− animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases. [ABSTRACT FROM AUTHOR]