Interleukin-38


Interleukin-38 is a member of the interleukin-36 cytokines group and interleukin-1 family. It is important for the inflammation process and host defense. This cytokine is known as IL-1HY2 in human and has similar three dimensional structure as IL-1 receptor antagonist. The organisation of IL-1HY2 gene is conserved with other members of IL-1 family and the location is in chromosome 2. IL-38 is produced by mammalian cells and it binds to IL-1 receptor type I. It is expressed in basal epithelia of skin, in proliferating B cells of the tonsil, in spleen and other tissues. This cytokine is playing important role in regulation of innate and adaptive immunity.

Discovery

IL-38 is probably originated from a common ancestral gene - an ancient IL-1Ra gene. This cytokine has 41% homology with IL-1Ra and 43% homology with IL-36Ra. IL-38 is expressed in skin, spleen, tonsil, thymus, heart, placenta and fetal liver. In tissues which do not play a special role in immune response, IL-38 is expressed in low quantity as other members of IL-1 family. In disease setting, specially when the activation of inflammatory response is dysregulated, the expression of IL-38 is changed. For example, in case of spondylitis ankylopoetica, cardiovascular disease, rheumatoid arthritis or hidradenitis suppurativa.

Processing and signaling

According to consensus of cleaving site of IL-1 family, it is predicted that two amino acids should be removed to generate a processed 3AA-152 IL-38 protein. The protease which cleaves IL-38 is still unknown as well as it is still not known which form of IL-38 is the natural variant present in the human body. It was reported that 20-152AA IL-38 form has increased biological activity.
IL-38 has characteristic dose-response curve and it binds to IL-36R. This cytokine is blocking Candida-induced interleukin-17 response better in low concentration than in higher concentration even if induction of cytokine is not blocked. So it is possible that IL-38 removed from the apoptotic cells can bind to the Three Immunoglobulin Domain-containing IL-1 receptor-related 2 with other name IL-1R9 and IL-38 will have in this case an antagonistic effect on induction of inflammatory cytokine. It is possible that IL-38 would be first ligand of TIGIRR-2.

Role in disease

Studies showed that IL-38 could play an important role in rheumatic diseases. IL-38 is also one of the five proteins which are related with C-reactive protein levels in the serum. The association of IL-38 with CRP could mean that IL-38 will play role also in inflammatory diseases as cardiovascular disease.

Function

The observation of knockdown of IL-38 with siRNA in peripheral blood mononuclear cells shows that production of interleukin-6, APRIL and CCL-2 were increased in response to TLR ligands, so IL-38 acted like antagonist in this case. There are also studies which show agonistic effect. In one study was compared the function of full-length IL-38 and truncated IL-38 and showed that high concentrations of the truncated IL-38 decreased production of IL-6 in response to interleukin-1β in human macrophages, while full-length form increased IL-6 in the same concentrations. So IL-38 could have agonistic and also antagonistic effects which depend on processing and concentration.
Also when spontaneous murine model of systemic lupus erythematosus was treated with recombinant IL-38, mice had less symptoms like proteinuria and skin lesions. Also serum levels of IL-17 and interleukin-22 were lower in these mice what approves in vitro observation that IL-38 could inhibit Th17 responses. Patients with SLE had higher concentrations of IL-38 in the serum than healthy patients and also patients with active disease had higher concentrations of IL-38 in the serum than patients with inactive form.
Sjogren's disease is disease related to SLE. Biopsy of gland of patients with primary Sjogren's disease shows that the expression of IL-38 was increased here. For modulation of this disease is important axis of IL-36. IL-38 is probably antagonist of IL-36 signaling similar as IL-36Ra what can play an important role in the pathogenesis of this autoimmune disease.
IL-38 was found also in the synovium of patients with rheumatoid arthritis and as well in mice with collagen-induced arthritis. IL-38 concentrations correlated with IL-1β. The overexpression of IL-38 in murine model of arthritis and serum transfer-induced arthritis ameliorate these diseases but not in case of antigen-induced arthritis. TNF production and IL-17 responses were decreased in these models. These data shows that IL-38 could have anti-inflammatory properties in rheumatoid arthritis and probably could be use in a therapeutic strategy.