The 5' untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women.

BACKGROUND: Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5' untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients. METHODS: Two novel IL1F10 5'UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations. RESULTS: A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found. CONCLUSIONS: The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.

IL-38 alleviates airway remodeling in chronic asthma via blocking the profibrotic effect of IL-36γ.

Airway remodeling is a major feature of asthma. Interleukin (IL)-36γ is significantly upregulated and promotes airway hyper-responsiveness (AHR) in asthma, but its role in airway remodeling is unknown. Here, we aimed to investigate the role of IL-36γ in airway remodeling, and whether IL-38 can alleviate airway remodeling in chronic asthma by blocking the effects of IL-36γ. IL-36γ was quantified in mice inhaled with house dust mite (HDM). Extracellular matrix (ECM) deposition in lung tissues and AHR were assessed following IL-36γ administration to mice. Airway inflammation, AHR, and remodeling were evaluated after IL-38 or blocking IL-36 receptor (IL-36R) treatment in asthmatic mice. The effects of lung fibroblasts stimulated with IL-36γ and IL-38 were quantified in vitro. Increased expression of IL-36γ was detected in lung tissues of HDM-induced asthmatic mice. The intratracheal instillation of IL-36γ to mice significantly enhanced the ECM deposition, AHR, and the number of activated lung fibroblasts around the airways. IL-38 or blocking IL-36R treated asthmatic mice showed a significant alleviation in the airway inflammation, AHR, airway remodeling, and number of activated fibroblasts around airways as compared with the HDM group. In vitro, IL-36γ promoted the activation and migration of human lung fibroblasts (HFL-1). The administration of IL-38 can counteract these biological processes induced by IL-36γ in HFL-1cells. The results indicated that IL-38 can mitigate airway remodeling by blocking the profibrotic effects of IL-36γ in chronic asthma. IL-36γ may be a new therapeutic target, and IL-38 is a potential candidate agent for inhibiting airway remodeling in asthma.

Association between IL-38 and inflammatory indicators in patients with bacterial pneumonia.

BACKGROUND: IL-38, a recently discovered cytokine of IL-1 family, exerts immunoregulatory activities in multi-type inflammatory diseases. However, its expression level and underlying clinical importance for IL-38 in respiratory bacterial infections remain unknown. METHODS: Thirty-five patients with bacterial pneumonia and twenty age- and gender- matched healthy individuals were enrolled in the study to determine serum IL-38 concentrations by ELISA. Then, the correlation between serum IL-38 levels and clinical features were analyzed and ROC curve was used to evaluate the potential diagnostic value for bacterial infections. In vitro, LPS-stimulated human respiratory epithelial cell model was employed to explore immunomodulatory mechanism of IL-38 in pulmonary infections. RESULTS: Elevated serum levels of IL-38 were determined in patients with bacterial pneumonia when compared with healthy controls. In addition, serum IL-38 levels were negatively correlated with clinical inflammation parameters, including WBC count, CRP, PCT and proinflammatory IL-6 and IL-8. In vitro, we demonstrated that recombinant IL-38 was able to remarkably inhibit expression of proinflammatory IL-6, IL-8, IL-1ß and TNF-α as well as adhesion molecule ICAM-1, which were partially mediated by attenuated activation of STAT3 and NF-κB signal cascades in BEAS-2B cells. Furthermore, we identified the diagnostic efficiency of IL-38 in discriminating patients with bacterial pneumonia from healthy individuals. CONCLUSIONS: Our study indicates higher serum IL-38 levels in patients with bacterial pneumonia are involved in anti-inflammatory activities in respiratory infections revealing a critical role of IL-38 in attenuating excessive pulmonary inflammation against exogenous pathogens. More importantly, IL-38 exhibited a potential novel biomarker for bacterial pneumonia. Thus, our data may provide useful insights for both clinical and basic research for bacterial pneumonia diagnosis.

Interleukin-36 cytokines are overexpressed in the skin and sera of patients with bullous pemphigoid.

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, ß, 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-36ß, 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 ß, 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.

Evaluation of interleukin-38 levels in serum of patients with coronavirus disease 2019.

Interleukin-38 (IL-38) has recently been considered as a cytokine with anti-inflammatory properties in viral respiratory infections, particularly coronavirus disease 19 (COVID-19), but the evidence has not been well elucidated. Therefore, a case-control study was conducted to determine IL-38 serum levels in 148 patients with COVID-19 (45 moderate, 55 severe, and 48 critical) and 113 controls. Results demonstrated that IL-38 levels did not show significant differences between patients and controls (68.7 [interquartile range: 62.7-75.6] vs. 67.7 [58.0-82.6] pg/ml; probability = 0.457). Similarly, patients stratified by disease severity, age group, gender, or chronic disease showed no significant differences between IL-38 levels in each stratum. Whereas, overweight/obese patients had a significantly lower median of IL-38 compared to normal-weight patients. Further, IL-38 showed significantly higher levels in the age group ≥50 years of patients with critical illness than in the age group <50 years. Female patients with severe disease also showed significantly elevated levels of IL-38 compared to male patients. In conclusion, the study indicated that serum IL-38 levels were not affected by COVID-19 infection, but the distribution of patients according to disease severity, age, gender, and body mass index may better reveal the role of IL-38 in disease pathogenesis.

IL-1 family cytokines as drivers and inhibitors of trained immunity.

Trained immunity is the long-term memory of innate immune cells, characterised by increased pro-inflammatory responses towards homo- and heterologous secondary stimuli. Interleukin (IL)-1 signalling plays an essential role in the induction of trained immunity, also called innate immune memory. As such, certain anti-inflammatory members of the IL-1 family of cytokines (IL-1F) which interfere with the inflammatory process have the potential to regulate the induction of a trained phenotype. The aim of this review is to provide an update on the role of IL-1F members in the context of trained immunity, emphasising the role of anti-inflammatory cytokines from the IL-1F to inhibit the induction of trained immunity, and touching upon their potential as therapeutics in IL-1-driven inflammatory disorders.

Low serum interleukin-38 levels in patients with Graves' disease and Hashimoto's thyroiditis.

BACKGROUND: Autoimmune thyroid disease (AITD) mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT), which is caused by individual genetics, autoimmune dysfunction, and a variety of external environmental factors. Interleukin (IL)-38 is involved in a wide range of autoimmune diseases, but little is known about IL-38 expression in AITD. METHODS: Fifty patients with GD, 50 with HT, and 50 healthy controls (HC) were enrolled in this study. Basic information of the participants was obtained through a physical examination. Immunological data were obtained by an automatic chemiluminescence immunoanalyzer. C-reactive protein (CRP) concentrations and the white blood cell count were measured. Serum IL-38 levels were determined by an enzyme-linked immunosorbent assay. RESULTS: Serum IL-38 levels were significantly lower in the GD and HT groups than in the HC group (both p < 0.01). Serum CRP concentrations were significantly lower in the HT group than in the HC group (p < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve was 0.7736 (p < 0.01) for IL-38 and 0.7972 (p < 0.01) for IL-38 combined with CRP in the GD group. In the HT group, the area under the curve was 0.7276 (p < 0.01) for IL-38 and 0.7300 for IL-38 combined with CRP (p < 0.01). CONCLUSIONS: The results suggest that serum IL-38 level is a potential new diagnostic biomarker in patients with GD and HT.

Biology of IL-38 and its role in disease.

IL-38 belongs to the IL-36 cytokines, which in turn are part of the IL-1 family. The first biological function of IL-38 described was blocking the activation of the IL-36R signaling similar to IL-36Ra. Since IL-36 cytokines require processing in order to become fully active, it is likely that IL-38 also must be processed to become maximally active. However, the protease(s) responsible for this is currently not known. In addition of IL-38 binding IL-36R, it has been proposed it can also interact with the co-receptor TIGIRR2. IL-38 is expressed in several tissues including tonsils, placenta, heart and brain, and IL-38 has been implicated in a wide variety of diseases including cardiovascular and autoimmune disease. Here, we discuss the discovery and biological function of IL-38, and its role in the pathogenesis of a wide variety of diseases.

The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease.

Interleukin (IL)-38 exerts an anti-inflammatory function by binding to several cytokine receptors, including the IL-36 receptor. In this study, we evaluated IL-38 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated its functions. IL-38 mRNA expression in endoscopic biopsy samples was evaluated using quantitative PCR. IL-38 protein expression was analyzed using immunohistochemical technique. Dextran sulfate sodium-induced colitis was induced in C57BL/6 background IL-38KO mice. The IL-38 mRNA and protein expression were enhanced in the active mucosa of ulcerative colitis, but not in Crohn's disease. The ratio of IL-36γ to IL-38 mRNA expression was significantly elevated in the active mucosa of UC patients. Immunofluorescence staining revealed that B cells are the major cellular source of IL-38 in the colonic mucosa. IL-38 dose-dependently suppressed the IL-36γ-induced mRNA expression of CXC chemokines (CXCL1, CXCL2, and CXCL8) in HT-29 and T84 cells. IL-38 inhibited the IL-36γ-induced activation of nuclear-factor kappa B (NF-κB) and mitogen-activated protein kinases in HT-29 cells. DSS-colitis was significantly exacerbated in IL-38KO mice compared to wild type mice. In conclusion, IL-38 may play an anti-inflammatory and protective role in the pathophysiology of IBD, in particular ulcerative colitis, through the suppression of IL-36-induced inflammatory responses.

Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment.

BACKGROUND: Interleukin (IL)-38 was discovered in 2001 and is a member of the IL-1 family of cytokines. IL-38 shows anti-inflammatory activity in several inflammatory diseases. In lung adenocarcinoma, we previously demonstrated that high IL-38 expression in tumor cells was associated with poor prognosis. However, the role of IL-38 in the tumor microenvironment has not been clarified. METHODS: IL-38-plasmid-transfected Lewis lung carcinoma cells (LLC-IL38) and empty vector-transfected LLC cells (LLC-vector) were established. Cell proliferation in vitro and tumor growth in vivo were examined, and immunohistochemical staining was used to assess tumor-infiltrating lymphocytes (TILs). A CD8+ lymphocyte depletion model was established to show the association between IL-38 and CD8+ lymphocytes. Moreover, we examined the association between IL-38 expression and CD8+ TILs in human samples, analyzing immunohistochemical staining in 226 patients with radically resected lung adenocarcinoma. RESULTS: Tumor growth of LLC-IL38 in vivo was significantly increased compared with that of LLC-vector, although cell proliferation of LLC-IL38 in vitro was lower than that of LLC-vector. CD8+ TILs were significantly decreased in LLC-IL38 tumor compared with LLC-vector tumor. The difference in tumor growth between LLC-IL38 and LLC-vector became insignificant after depletion of CD8+ lymphocytes. In immunohistochemical staining in tissues from patients with lung adenocarcinoma, multivariate analysis showed high IL-38 expression was an independent negative predicter of high density of CD8+ TILs. CONCLUSION: We demonstrated that high IL-38 expression in tumor cells was significantly associated with reduction of CD8+ TILs and tumor progression. These results suggest that IL-38 could be a therapeutic target for lung cancer.

IL-38 as an early predictor of the ischemic stroke prognosis.

BACKGROUND: Ischemic stroke is caused by a sudden neurological defect following a vascular occlusion and elicits a local and systemic inflammation in brain tissue. Interleukin-38 is an anti-inflammatory cytokine associated with ischemic and inflammatory diseases. This study was designed to analyze the effect of tPA therapy on interleukin-38 serum level changes and the serum level of IL-38 in the prognosis of ischemic stroke patients in the next three months. METHODS: We enrolled 29 ischemic stroke patients confirmed by a neurologist based on radiologic and clinical manifestation between 2019 September to 2020 February. The patients who had NIHSS more than 6 with no underlying inflammatory diseases were selected for tPA therapy. On admission and 24 h after tPA therapy, the IL-38 serum level was measured by ELISA kit. RESULTS: The results showed that serum levels of IL-38 were significantly increased after tPA therapy (P < 0.001). A remarkable relationship was observed between the modified Rankin Score (mRS) and IL-38 serum changes in response to tPA therapy (P < 0.001). Besides, IL-38 serum changes following tPA were dramatically related to NIHSS at hospitalization (P = 0.007). Also, our analysis posed a positive relation between NIHSS at hospitalization and mRs criteria (P = 0.023). No notable relation has been observed between IL-38 serum levels before and after tPA and mRs (P = 0.601 and P = 0.074, respectively). Furthermore, there was no evidence for the relation between NIHSS at hospitalization and IL-38 levels before and after tPA (P = 0.457 and P = 0.105, respectively). CONCLUSION: The results indicate that tPA could meaningfully increase the IL-38 serum level. Also, a negative correlation has been found between IL-38 serum changes in response to tPA and mRS. Since the lower changes in IL-38 serum level result in a poorer prognosis, we conclude that IL-38 serum changes might be a novel early predictor factor for ischemic stroke prognosis.

Human recombinant interleukin-38 suppresses inflammation in mouse models of local and systemic disease.

Interleukin (IL)-38 belongs to the IL-1 family and is part of the IL-36 subfamily due to its binding to the IL-36 Receptor (IL-1R6). In the current study, we assessed the anti-inflammatory properties of IL-38 in murine models of arthritis and systemic inflammation. First, the anti-inflammatory properties of mouse and human IL-38 precursors were compared to forms with a truncated N-terminus. In mouse bone marrow derived dendritic cells (BMDC), human and mouse IL-38 precursors with a truncation of the two N-terminal amino acids (3-152) suppressed LPS-induced IL-6. Recombinant human IL-38 (3-152) was further investigated for its immunomodulatory potential using four murine models of inflammatory disease: streptococcal cell wall (SCW)-induced arthritis, monosodium urate (MSU) crystal-induced arthritis, MSU crystal-induced peritonitis, and systemic endotoxemia. In each of these models IL-38 significantly reduced inflammation. In SCW and MSU crystal-induced arthritis, joint swelling, inflammatory cell influx, and synovial levels of IL-1ß, IL-6, and KC were reduced by 50% or greater. These suppressive properties of IL-38 in SCW-induced arthritis were independent of the anti-inflammatory co-receptor IL-1R8, as IL-38 reduced arthritis equally in IL-1R8 deficient and WT mice. In MSU crystal-induced peritonitis, IL-38 reduced hypothermia, while plasma IL-6 and KC and peritoneal KC levels were reduced by 65-70%. In the LPS endotoxemia model, IL-38 pretreatment reduced systemic IL-6, TNFα and KC. Furthermore, in ex vivo cultured bone marrow, LPS-induced IL-6, TNFα and KC were reduced by 75-90%. Overall, IL-38 exhibits broad anti-inflammatory properties in models of systemic and local inflammation and therefore may be an effective cytokine therapy.

Immunobiological Properties and Clinical Applications of Interleukin-38 for Immune-Mediated Disorders: A Systematic Review Study.

Exponential growth in the usage of "cytokines" (as seroimmunobiomarkers) has facilitated more accurate prognosis, early diagnosis, novel, and efficient immunotherapeutics. Numerous studies have reported immunopathophysiological and immunopathological processes of interleukin-38 (IL-38). Therefore, in this systematic review article, the authors aimed to present an updated comprehensive overview on the immunobiological mechanisms, diagnostic, and immune gene-based therapeutic potentials of IL-38. According to our inclusion and exclusion criteria, a total of 216 articles were collected from several search engines and databases from the January 2012 to July 2021 time interval by using six main keywords. Physiologic or pathologic microenvironments, optimal dosage, and involved receptors affect the functionalities of IL-38. Alterations in serum levels of IL-38 play a major role in the immunopathogenesis of a wide array of immune-mediated disorders. IL-38 shows anti-inflammatory activities by reduction or inhibition of pro-inflammatory cytokines, supporting the therapeutic aspects of IL-38 in inflammatory autoimmune diseases. According to the importance of pre-clinical studies, it seems that manipulation of the immune system by immunomodulatory properties of IL-38 can increase the accuracy of diagnosis, and decipher optimal clinical outcomes. To promote our knowledge, more collaboration is highly recommended among laboratory scientists, internal/infectious diseases specialists, oncologists, immunologists, diseases-specific biomarkers scientists, and basic medical researchers.

Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients.

OBJECTIVE: Interleukin (IL)-38 is a newly discovered member of the IL-1 cytokine family with a proposed anti-inflammatory profile. We studied the probable role of this cytokine in the pathogenesis of two autoimmune diseases: multiple sclerosis (MS) and systemic sclerosis (SSc). SUBJECTS AND METHODS: A total of 87 MS patients and 86 SSc patients (40 new and recently untreated cases and 46 treated cases) were selected for this study. Eighty-seven and 80 age- and sex-matched healthy subjects were included as controls for MS and SSc, respectively. Clinical and paraclinical features of the patients were recorded at the time of sampling. Serum IL-38 was measured by ELISA. RESULTS: Levels of serum IL-38 did not significantly differ between the total MS or SSc patients compared to controls. However, levels of IL-38 were significantly higher in newly diagnosed patients of MS (206.43 ± 38.97 pg/mL, p < 0.0001) than in those previously treated (158.04 ± 39.45 pg/mL). Similarly, new/recently untreated cases of SSc patients showed increased IL-38 levels (185.19 ± 36.27 pg/mL, p = 0.001) compared to treated patients (166.82 ± 33.08 pg/mL). IL-38 levels in newly diagnosed MS patients (p = 0.007) and new/recently untreated SSc patients (p = 0.032) were significantly higher than those in healthy controls. CONCLUSION: The higher serum levels of IL-38 in new or recently untreated cases of MS and SSc patients than in treated patients and healthy controls suggest the possible role of this cytokine in the development of these diseases or as part of a feedback loop to attenuate the inflammatory conditions in early stages of these diseases.

Interleukin-38 alleviates cardiac remodelling after myocardial infarction.

Excessive immune-mediated inflammatory reaction plays a deleterious role in ventricular remodelling after myocardial infarction (MI). Interleukin (IL)-38 is a newly characterized cytokine of the IL-1 family and has been reported to exert a protective effect in some autoimmune diseases. However, its role in cardiac remodelling post-MI remains unknown. In this study, we found that the expression of IL-38 was increased in infarcted heart after MI induced in C57BL/6 mice by permanent ligation of the left anterior descending artery. In addition, our data showed that ventricular remodelling after MI was significantly ameliorated after recombinant IL-38 injection in mice. This amelioration was demonstrated by better cardiac function, restricted inflammatory response, attenuated myocardial injury and decreased myocardial fibrosis. Our results in vitro revealed that IL-38 affects the phenotype of dendritic cells (DCs) and IL-38 plus troponin I (TNI)-treated tolerogenic DCs dampened adaptive immune response when co-cultured with CD4+ T cells. In conclusion, IL-38 plays a protective effect in ventricular remodelling post-MI, one possibility by influencing DCs to attenuate inflammatory response. Therefore, targeting IL-38 may hold a new therapeutic potential in treating MI.

Interleukin-38 protects against sepsis by augmenting immunosuppressive activity of CD4+ CD25+ regulatory T cells.

Naturally occurring CD4+ CD25+ regulatory T cells (Tregs) are required to limit immune-induced pathology and to maintain homeostasis during the early-phase of sepsis. This study aimed to investigate the role of interleukin (IL)-38, a newly described member of the IL-1 cytokine family, in mediated immune response of CD4+ CD25+ Tregs in sepsis. Here, we provide evidence that expressions of IL-38 and its receptor were detected in murine CD4+ CD25+ Tregs. Stimulation of CD4+ CD25+ Tregs with LPS markedly up-regulated the expression of IL-38. Treatment with rmIL-38 dramatically enhanced the immunosuppressive activity of CD4+ CD25+ Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti-IL-38 antibody was administered. Administration of rmIL-38 improved the survival rate of CLP mice. In addition, CD4+ CD25+ Tregs depletion before the onset of sepsis obviously abolished IL-38-mediated protective response. These findings suggest that IL-38 enhances the immunosuppressive activity of CD4+ CD25+ Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis.

Interleukin-38 is elevated in inflammatory bowel diseases and suppresses intestinal inflammation.

There has been no report investigating the role of IL-38 in inflammatory bowel diseases (IBD). Therefore, we investigated the expression of IL-38 in IBD patients and its role in regulating intestinal inflammation. The levels of IL-38 were significantly elevated in the intestine of IBD patients and DSS-induced colitis mice. Immunofluorescence analysis revealed that B cell, not macrophage or T cell, was the source of IL-38 in the intestine. We found that rIL-38 treatment significantly attenuated DSS-induced colitis, including alleviation of weight loss, disease activity index, macroscopic changes and histological damage of colon, along with lower levels of IL-1ß and TNF-α. In vitro, rIL-38 significantly decreased the expression of proinflammatory cytokines in LPS-stimulated RAW 264.7 cells and BMDM. This is the first study suggesting that IL-38 may have a protective effect in IBD, which inhibits the production of proinflammatory cytokines from macrophages. IL-38 may represent a promising therapeutic strategy in IBD.

Interleukin-38 inhibits adipogenesis and inflammatory cytokine production in 3T3-L1 preadipocytes.

Interleukin-38 (IL-38) is a novel member of the IL-1 cytokine family with anti-inflammatory activity. However, its effect on adipogenesis and inflammatory cytokines secretion of adipocytes in vitro has not been reported. To address whether IL-38 inhibits adipogenesis and inflammation in vitro, adipose precursor 3T3-L1 cells were cultured with or without IL-38. The morphology and size of lipid droplets in 3T3-L1 cells were measured by Oil red O staining. The mRNA expression levels of GATA-binding protein-3 (GATA-3), glucose transporter type 4 (GLUT4), peroxisome proliferator-associated receptor γ2, IL-1ß, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in 3T3-L1 cells were detected by real-time PCR, The contents of IL-6, IL-1ß, and MCP-1 in 3T3-L1 cell medium supernatants were determined by enzyme-linked immunosorbent assay. IL-38 significantly decreased the number of lipid droplets in 3T3-L1 cells. IL-38 also increased GATA-3 and GLUT4 mRNA expression and inhibited IL-1ß, IL-6, and MCP-1 secretion by 3T3-L1 cells. It is concluded that IL-38 can inhibit the differentiation of human adipocytes and inflammatory cytokine production by 3T3-L1 cells.

IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential.

The interleukin (IL)-1 family of cytokines is composed of 11 members, including the most recently discovered IL-36α, ß, γ, IL-37, and IL-38. Similar to IL-1, IL-36 cytokines are initiators and amplifiers of inflammation, whereas both IL-37 and IL-38 display anti-inflammatory activities. A few studies have outlined the role played by these cytokines in several inflammatory diseases. For instance, IL-36 agonists seem to be relevant for the pathogenesis of skin psoriasis whereas, despite being expressed within the synovial tissue, their silencing or overexpression do not critically influence the course of arthritis in mice. In this review, we will focus on the state of the art of the molecular features and biological roles of IL-36, IL-37, and IL-38 in representative skin- and joint-related inflammatory diseases, namely psoriasis, rheumatoid arthritis, and psoriatic arthritis. We will then offer an overview of the therapeutic potential of targeting the IL-36 axis in these diseases, either by blocking the proinflammatory agonists or enhancing the physiologic inhibitory feedback on the inflammation mediated by the antagonists IL-37 and IL-38.

[Correlation between serum interleukin-38 and acute exacerbation of chronic obstructive pulmonary disease with pulmonary embolism].

Objective: To investigate the correlation between serum interleukin-38 (IL-38) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with pulmonary embolism (PE). Methods: The 94 patients with AECOPD admitted to Tianjin Chest Hospital from August 2015 to April 2018 were suspected of PE. They were divided into two groups based on CT pulmonary angiography (CTPA) and color Doppler ultrasound of lower extremity veins: 39 cases in PE group and 55 cases in Non-PE group. The general data and laboratory examination results of these subjects were recorded. Serum IL-38 was measured by double antibody enzyme-linked immunosorbent assays (ELISA). The between-group differences of above parameters were analyzed. Pearson correlation or Spearman rank correlation was used to analyze the association of IL-38 with each variable in AECOPD patients. Binary Logistic regressions were conducted to determine the risk factors of AECOPD with PE. ROC curve was used to assess the value of serum IL-38 in predicting AECOPD with PE. Results: The serum level of IL-38 was lower in PE group than in Non-PE group [46.3 (33.1, 58.1) vs 61.5 (46.6, 72.5) ng/L, P<0.05]. Correlation analysis showed that serum IL-38 levels were negatively correlated with C reactive protein and fibrinogen in patients with AECOPD (r=-0.38,-0.29, all P<0.05). Binary Logistic regressions showed that lower serum IL-38 level was a risk factor of AECOPD with PE (OR=0.78, 95%CI: 0.61-0.94, P<0.05). The area under the ROC curve was 0.74 (95% CI: 0.63-0.84, P<0.05). When cutoff value of serum IL-38 was 52.1ng/L, the sensitivity was 70.9% and the specificity was 69.2% respectively. Conclusion: IL-38 could relieve the hypercoagulability by inhibiting inflammation in patients with AECOPD and could act as a predictor of AECOPD with PE.