Role Of IL-36 Cytokines Research Articles

Role of IL-36 cytokines in psoriasis and other inflammatory skin conditions.

The IL-36 family of cytokines includes three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ) and a receptor antagonist (IL-36Ra), which bind and signal through a heterodimeric receptor composed of IL-36R and the IL-1R accessory protein (IL-1RAcP). Individuals with inactivating mutations in the gene encoding IL-36Ra develop generalized pustular psoriasis, a severe form of psoriasis, a finding which clearly links dysregulated IL-36 pathway activation to inflammatory skin conditions. The purpose of this review is to highlight the cellular source of IL-36 cytokines, the effects of IL-36 signaling across cell types, and the association of IL-36 to a spectrum of inflammatory skin diseases including various forms of psoriasis as well as hidradenitis suppurativa, atopic dermatitis, and allergic contact dermatitis.

Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases.

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

Role of IL-36 Cytokines in the Regulation of Angiogenesis Potential of Trophoblast Cells.

IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines (HTR-8/SVneo and JEG-3) and upon treatment with bacterial and viral components. Effects of recombinant IL-36 on the migration capacity of trophoblastic cells, their ability to interact with endothelial cells and the induction of angiogenic factors and miRNAs (angiomiRNAs) were examined. Constitutive protein expression of IL-36 (α, β, and γ) and their receptor (IL-36R) was found in all cell types. In PTC, transcripts for all IL-36 subtypes were found, whereas in trophoblastic cell lines only for IL36G and IL36RN. A synthetic analog of double-stranded RNA (poly I:C) and lipopolysaccharide (LPS) induced the expression of IL-36 members in a cell-specific and time-dependent manner. In HTR-8/SVneo cells, IL-36 cytokines increased cell migration and their capacity to interact with endothelial cells. VEGFA and PGF mRNA and protein, as well as the angiomiRNAs miR-146a-3p and miR-141-5p were upregulated as IL-36 response in PTC and HTR-8/SVneo cells. In conclusion, IL-36 cytokines are modulated by microbial components and regulate trophoblast migration and interaction with endothelial cells. Therefore, a fundamental role of these cytokines in the placentation process and in response to infections may be expected.

Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease

Interleukin (IL)-36α, IL-36β and IL-36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL-36Ra or IL-38, another potential IL-36 inhibitor, limit uncontrolled inflammation. The expression and role of IL-36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38 mRNA, was induced and correlated with IL-1β and T helper type 17 (Th17) cytokines (IL-17A, IL-22, IL-23, CCL20). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1β, CCL3, CCL4 and macrophage colony-stimulating factor (M-CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at relatively low levels and correlated with IL-1β and IL-17A. We suggest that only a minor subgroup of patients with RA (17-29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL-36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL-36β and IL-36Ra were produced constitutively, but IL-36α, γ and IL-38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL-36 agonists/antagonists ratio.