Abstract
Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.
Highlights
Interleukin-1 family (IL-1F) members comprise a total of 11 pro-inflammatory cytokines, including IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, and IL-36γ, and anti-inflammatory cytokines, including IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38 [1]
The IL-38/interleukin-36 receptor (IL-36R) axis performs its anti-inflammatory function by suppressing proinflammatory cytokines from Mφs, peripheral blood mononuclear cells (PBMCs) or fibroblast-like synoviocytes (FLSs), and Rheumatoid arthritis (RA)-synovial fibroblasts (SFs) induced by IL-1β significantly induce inflammation, indicating that IL-38/interleukin-1 receptor 1 (IL-1R1) may be involved in this process
IL-36 procytokines and IL-36Ra levels are further increased at the peak of psoriasis in a mouse model induced by IMQ, a TLR7 agonist that activates the innate immune response and induces skin inflammation, IL-38 expression is reduced dramatically at the same time, these findings are in accordance with those observed in psoriasis patients [29]
Summary
Interleukin-1 family (IL-1F) members comprise a total of 11 pro-inflammatory cytokines, including IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, and IL-36γ, and anti-inflammatory cytokines, including IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38 [1]. Inflammatory autoimmune diseases and self-reactive, pathological immune disorders involving the attack of autologous organs, tissues, and cells [17,18] are very common, and both heredity factors and the environment have vital roles in their pathogenic mechanisms [19,20]. Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), chronic lymphocytic thyroiditis, systemic scleroderma (SSc), primary Sjogren’s syndrome (pSS), psoriasis, and inflammatory bowel disease (IBD) are among the most common inflammatory autoimmune diseases. These diseases, which are a public health problem, are chronic and incurable, leading to both significant individual suffering and a societal burden [19]. We summarize the current knowledge concerning the roles of IL-38 in several inflammatory autoimmune diseases and discuss the therapeutic potential of targeting IL-38
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