interleukin-38 interleukin-38 interleukin-38 (il-38) is a member of the interleukin-1 (il-1) family and the interleukin-36 (il-36) subfamily. it is important for the inflammation and host defense. this cytokine is named il-1f10 in humans and has similar three dimensional structure as il-1 receptor antagonist (il-1ra). the organisation of il-1f10 gene is conserved with other members of il-1 family within chromosome 2q13. il-38 is produced by mammalian cells may bind the 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 probably originated from a common ancestral gene - an ancient il-1rn 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 similar to other members of the 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 (aa) should be removed to generate a processed 3-152aa 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 non-characteristic dose-response curve and it binds to il-36r (il-1r6). this cytokine is blocking candida-induced interleukin-17 (il-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 released by apoptotic cells can bind to the three immunoglobulin domain-containing il-1 receptor-related 2 (tigirr-2, gene name il1rapl1, also known as 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, a former orphan receptor of the il-1 family. 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 (crp) 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 (il-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 (il-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 (sle) 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 (cia). 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.