IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

Teng, Xiu; Hu, Zhonglan; Wei, Xiaoqiong; Wang, Zhen; Guan, Ting; Liu, Ning; Liu, Xiao; Ye, Ning; Deng, Guohua; Luo, Can; Huang, Nongyu; Sun, Conroy; Xu, Minyan; Zhou, Xikun; Deng, Hongxin; Edwards, Carl K.; Chen, Xiancheng; Wang, Xiaoxia; Cui, Kaijun; Wei, Yuquan; Li, Jiong

doi:10.4049/jimmunol.1300047

Cited by 158 publications

(147 citation statements)

References 59 publications

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“…The inhibitory effects of IL-37 on innate immune response have been studied using cells transfected or silenced with IL-37, mice treated with recombinant or plasmid-DNA IL-37, and IL-37tg mice (2,3,(8)(9)(10)(11)(12). In the present study, we not only demonstrated the inhibitory effects of IL-37 on adaptive immune response, but also provided evidence that IL-37 promotes generation of semimature tolerogenic DCs.…”

Section: Discussionsupporting

confidence: 63%

See 1 more Smart Citation

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

Luo¹,

Cai

Liu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

156

177

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IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS-induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (−61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice (−60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1β, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8 + T cells (−74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity.tolerance | skin inflammation | allergic contact dermatitis I nterleukin-37 (IL-37; formerly IL-1 family member 7) isoform b inhibits innate inflammation (1-3). In human peripheral blood from healthy subjects, low levels of steady-state IL-37 mRNA and protein are expressed in monocytes, dendritic cells (DCs), and plasma cells perhaps due to instability elements within the coding region (4, 5); however, stimulation with proinflammatory cytokines or Toll-like receptor (TLR) ligands induces IL-37 levels, which in turn suppress the proinflammatory cytokines IL-1α, IL-1β, IL-6, M-CSF, and GM-CSF but not anti-inflammatory cytokines IL-10 and IL-1Ra (4-7). Although an ORF for the murine homolog of IL37 is absent in various mouse databases, human IL-37 expression in a variety of human and murine cells inhibits innate immunity and suppresses production of proinflammatory cytokines and chemokines (2,3,8), indicating that human IL-37 is functional in murine cells. Compared with WT mice, mice expressing human IL-37b (IL-37tg mice) produce lower amounts of proinflammatory cytokines after lipopolysaccharide (LPS) administration and are protected from LPS-induced septic shock (3) and dextran sulfate sodium-induced colitis (8). Administration of recombinant human IL-37 in mice suppresses cytokine and chemokine production, neutrophil infiltration, and cell death, thereby ameliorating hepatic and myocardial ischemia/reperfu...

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Section: Discussionsupporting

confidence: 63%

“…Administration of recombinant human IL-37 in mice suppresses cytokine and chemokine production, neutrophil infiltration, and cell death, thereby ameliorating hepatic and myocardial ischemia/reperfusion injury (9,10). Treatment of mice with human IL-37 plasmid-DNA reduces local and systemic inflammation in Con A-induced hepatitis and psoriasis (11,12).…”

mentioning

confidence: 99%

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

Luo¹,

Cai

Liu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

156

177

View full text Add to dashboard Cite

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“…In vivo, mice transgenic for IL-37 exhibited markedly reduced production of IL-17 and other proinflammatory cytokines, including IL-1b and IL-6, following LPS stimulation (11). Other studies showed that IL-37 is strongly expressed by CD4 + T cells and macrophages in human psoriatic plaques, which may inhibit the excessive inflammation in the pathogenesis of psoriasis (12). Based on the data described above, it is postulated that IL-37, through the production of activated immune cells, may play a prominent role in the pathogenesis of RA by curbing IL-17 or other proinflammatory cytokines.…”

mentioning

confidence: 99%

IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17–Triggering Cytokine Production and Limiting Th17 Cell Proliferation

Ye¹,

Jiang²,

Deng

et al. 2015

The Journal of Immunology

138

127

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IL-37, a new member of the IL-1 cytokine family, is a natural inhibitor of innate immunity associated with autoimmune diseases. This study was undertaken to evaluate whether IL-37 has antiarthritic effects in patients with rheumatoid arthritis (RA) and in mice with collagen-induced arthritis (CIA). In this study, we analyzed the expression of IL-37 in PBMCs, serum, and lymphocytes from RA patients as well as CD4+ T cells polarized under Th1/Th2/Th17 conditions. The role of IL-37 was assessed by investigating the effects of recombinant human (rh)IL-37 and an adenovirus encoding human IL-37 (Ad–IL-37) on Th17 cells and Th17-related cytokines in RA patients and CIA mice. We found that active RA patients showed higher IL-37 levels compared with patients with inactive RA and healthy controls. Upregulated IL-37 expression also was found in CD3+ T cells and CD4+ T cells from RA patients and in Th1/Th17-differentiation conditions. rhIL-37 markedly decreased IL-17 expression and Th17 cell frequency in PBMCs and CD4+ T cells from RA patients. Furthermore, IL-37 exerted a more suppressive effect on Th17 cell proliferation, whereas it had little or no effect on Th17 cell differentiation. IL-17 and IL-17–driving cytokine production were significantly reduced in synovium and joint cells from CIA mice receiving injections of Ad–IL-37. Our findings indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of human RA and CIA models via the downregulation of IL-17 and IL-17–triggering cytokine production and the curbing of Th17 cell proliferation.

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“…2 Although its biological function is not elucidated completely, many studies indicate a protective role of IL37 on immunopathogenesis through reducing anti-inflammatory cytokines from innate immune cells. 22 Here to better understand this Figure 3 The dN/dS ratios of different evolutionary lineages in primates. Phylogenetic tree was constructed using neighbor-joining method using IL37 orthologous sequences from multiple species.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we propose that the biological functions of IL37 variants need to be verified and compared with earlier experimental results using NCBI reference protein. 4,8,22 Second, our data provides valuable guidance on picking SNPs for disease association studies. Previous reports suggested that IL37 was involved in the development of various inflammatory conditions, including ankylosing spondylitis and rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-37 gene variants segregated anciently coexist during hominid evolution

et al. 2015

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IL37 is a member of IL-1 cytokine family but conveys anti-inflammatory functions. The biological characteristic and genetic heterogeneity of IL37 are not fully understood yet. Here using the whole-genome sequencing data from 1000 Genomes Project, we performed population and evolutionary genetic analysis of human IL37 gene. First, 2184 IL37 gene sequences from different human populations were retrieved. The IL37 protein sequences were inferred from the coding DNA sequences and multiple species alignment was made. Then, the phylogenetic tree of IL37 was built and dN/dS ratios were calculated for each evolutionary branch, the classic McDonald and Kreitman test was also performed. Next, we conducted intraspecific evolutionary genetic analysis and built the genealogy network of 116 unique IL37 haplotypes through median-joining network analysis. Finally, we compared IL37 sequences between the modern and archaic humans. Our results for the first time provide solid evidence that common IL37 variants other than NCBI reference sequence are present worldwide. Our data also supports that IL37 variants are shaped and maintained by selection instead of neutral evolution. We further identified that human IL37 variants consist of two major haplogroups and their presence in archaic humans corroborates its ancient origin in hominid evolution. In conclusion, these data indicate that common IL37 variants are maintained among human populations by selective force, suggesting their potential involvements in immune regulation and human diseases. In addition, the ancient history of IL37 variants reveals interesting insight into the complicated human evolutionary history.

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IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

Cited by 158 publications

References 59 publications

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17–Triggering Cytokine Production and Limiting Th17 Cell Proliferation

Interleukin-37 gene variants segregated anciently coexist during hominid evolution

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