IL-38 is a biomarker for acute respiratory distress syndrome in humans and down-regulates Th17 differentiation in vivo

Chai, Yu-sen; Lin, Shihui; Zhang, Mu; Deng, Liangyong; Chen, Yanqing; Xie, Kexin; Wang, Chuanjiang; Xu, Fang

doi:10.1016/j.clim.2019.108315

Cited by 22 publications

(19 citation statements)

References 38 publications

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“…It has been reported that upregulated IL-38 can improve the survival in sepsis by targeting suppressive CD4+CD25+ regulatory T (Treg) 21,22 . Importantly, in a lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) induced ARDS model, IL-38 has been proven to be protective by down-regulating Th17 differentiation 23 . Besides, IL-38 protein was found to be overexpressed in the lungs of patients with idiopathic pulmonary fibrosis and lung adenocarcinoma 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections

et al. 2021

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Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.

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Section: Introductionmentioning

confidence: 99%

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections

et al. 2021

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“…In an in vitro study, Chai et al . demonstrated that Th17 cells differentiation and IL-17 production have no significant changes after the treatment with Anti-IL-38 Abs, while IL-38 recombination protein can significantly decrease percentages of Th17 cells through the suppression of p-STAT3 (another important transcription factor of Th17 cells) [ 33 ]. Since there is no expression of IL-38 in mouse CD4 + T cells, but mouse CD4 + T cells display surface expression of IL-36R (IL-38 specific receptor) [ 10 , 11 ], making them capable of receiving the biological signal of IL-38 released by a large number of infiltrated immune cells (e.g., B cells, NK cells, macrophages, and DCs) during the acute phase of infection, this may be an important mechanism by which Anti-IL-38 Abs participate in the regulation of Th cells differentiation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice

Xue

Chen

et al. 2021

Virol J

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Background Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated. Methods Male BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORγt) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected. Results The mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORγt expression. Down-regulation of IFN-γ and up-regulation of IL-17, TNF-α, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication. Conclusions Neutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC.

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“…IL-38 is a new type of anti-in ammatory cytokine, which has an anti-in ammatory effect in in ammatory bowel disease [13], osteoarthritis [14], sepsis [15], and other in ammatory diseases [16]. Our previous studies found that in the model of cecal ligation and puncture (CLP)-induced ARDS, IL-38 played a protective role by downregulating the differentiation of Th17 [17]. In this study, we rst observed a signi cant increase in IL-38 levels during the early stages of clinical P.A.…”

Section: Discussionmentioning

confidence: 99%

“…Serum samples were then divided evenly into the Eppendorf (EP) tubes and preserved at -80 °C for subsequent experiments. The ELISA test kit (R&D Systems, California, USA, # DY9110-05) was used for measuring IL-38 levels according to a previous method [17]. Serum levels of IL-6, IL-8, IL-10, IL-17, IL-1β, and TNF-α were detected at the Clinical Testing Center of The First A liated Hospital of Chongqing Medical University.…”

Section: Human Subjectsmentioning

confidence: 99%

“…Recent studies have found that IL-38 can competitively bind to IL-1R1, preventing IL-1R accessory protein (IL-1RAcP) recruitment, and causing anti-in ammation in in ammatory bowel disease (IBD) [13], osteoarthritis (OS) [14], sepsis [15], and other in ammatory diseases [16]. Previous research by our group showed that IL-38 protects the cecal ligation and punctures the (CLP)-or lipopolysaccharide (LPS)-mediated acute respiratory distress syndrome (ARDS) model by reducing Th17 differentiation [17].…”

Section: Introductionmentioning

confidence: 99%

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Contribution of IL-38 in Lung Immunity During Pseudomonas Aeruginosa-Induced Pneumonia

Wei

Chen

Wang

2021

Preprint

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Objective: Interleukin-38 (IL-38), a new type of cytokine, is involved in processes such as tissue repair, inflammatory response, and immune response. However, its function in pneumonia caused by Pseudomonas aeruginosa is still unclear.Methods: In this study, we detected circulating IL-38 in adults affected by pneumonia caused by P. aeruginosa. The P. aeruginosa-induced pneumonia WT murine model was adopted to evaluate the effect of IL-38 on Treg differentiation, cell apoptosis, survival, tissue damage, inflammation, and bacterial removal.Results: IL-38 is insufficiently secreted in patients who died of P.A. pneumonia.Recombinant IL-38 improved survival, whereas anti-IL-38 antibody reduced survival in the experimental pneumonia murine model. IL-38 exposure reduced the inflammatory response, as suggested by the lung injury, and reduced cytokine levels (IL-1β, IL-6, IL-17A, TNF-α, and CXCL-1, but not IL-10). It also increased bacterial clearance and reduced cell apoptosis in the lungs. Furthermore, IL-38 was shown to reduce TBK1 expression in vitro when naïve CD4+ T lymphocytes were differentiated to Tregs and played a protective role in P.A. pneumonia.Conclusions: To summarize, the above findings provide additional insights into the mechanism of IL-38 in the treatment of P.A. pneumonia.

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IL-38 is a biomarker for acute respiratory distress syndrome in humans and down-regulates Th17 differentiation in vivo

Cited by 22 publications

References 38 publications

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections

Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice

Contribution of IL-38 in Lung Immunity During Pseudomonas Aeruginosa-Induced Pneumonia

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