Abstract
The IL-36 subfamily of cytokines belongs to the IL-1 superfamily and consists of three pro-inflammatory agonists IL-36α, IL-36β, IL-36γ, and an IL-36 receptor (IL-36R) antagonist, IL-36Ra. These IL-36 cytokines function through a common receptor to modulate innate and adaptive immune responses. IL-36 cytokines are expressed as inactive precursors and require proteolytic processing to become fully active. Upon binding to IL-36R, IL-36 agonists augment the expression and production of inflammatory cytokines via activating signaling pathways. IL-36 is mainly expressed in epidermal, bronchial, and intestinal epithelial cells that form the barrier structures of the body and regulates the balance between pro-inflammatory and anti-inflammatory cytokine production at these tissue sites. Dysregulation of IL-36 signaling is a major etiological factor in the development of autoimmune and inflammatory diseases. Besides its critical role in inflammatory skin diseases such as psoriasis, emerging evidence suggests that aberrant IL-36 activities also promote inflammatory diseases in the lung, kidneys, and intestines, underscoring the potential of IL-36 as a therapeutic target for common inflammatory diseases. The role of IL-36 signaling in cancer development is also under investigation, with limited studies suggesting a potential anti-tumor effect. In this comprehensive review, we summarize current knowledge regarding the expression, activation, regulatory mechanisms, and biological functions of IL-36 signaling in immunity, inflammatory diseases, and cancer development.
Highlights
The interleukin-1 (IL-1) cytokine family is comprised of immune-activating cytokines that regulate intercellular communication during an immune response
Experimental studies of collagen-induced arthritis (CIA), antigen-induced arthritis, tumor necrosis factor (TNF)-induced arthritis, and K/BxN serum transferinduced arthritis of mice show that IL-36 (α, β, and γ ) and IL-36 receptor (IL-36R) are present, but blockade of IL-36R or IL-36R−/− mice led to no improvement in arthritis. These findings suggest that the severity of experimental arthritis is independent of IL-36R, but the cytokine is likely still contributing to the inflammation (Lamacchia et al, 2013; Derer et al, 2014)
In order to maintain a healthy tissue state, IL-36 cytokines are regulated by their natural antagonist, IL-36Ra, which prevents hyperinflammation of the corresponding tissue
Summary
The interleukin-1 (IL-1) cytokine family is comprised of immune-activating cytokines that regulate intercellular communication during an immune response. IL-36R is highly expressed in human M0 and M2 macrophages, but not in M1 macrophages Consistent with this pattern, IL-36 stimulation increases production of inflammatory cytokines from M2 macrophages and directs them to a proinflammatory phenotype but has no effect on M1 macrophages (Dietrich et al, 2016). IL-36Ra is highly expressed in the skin, brain, tonsils, spleen, and various immune cell types such as macrophages, monocytes, B cells, and DCs (Mulero et al, 1999; Smith et al, 2000; Debets et al, 2001; Carrier et al, 2011; FIGURE 1 | (A) Schematic illustration of the human IL-1 family gene cluster. The phylogenetic tree was generated based on protein sequence alignment using Cobalt tool (www.ncbi.nlm.nih.gov/tools/cobalt/re_cobalt.cgi) with Cladogram tree method and default settings
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