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.[1]
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.[9]
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.[10] 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.[9]
Role in disease
Studies showed that IL-38 could play an important role in rheumatic diseases.[11][12][13] IL-38 is also one of the five proteins which are related with
C-reactive protein (CRP) levels in the
serum.[14] 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 bloodmononuclear 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.[15] There are also studies which show agonistic effect.[9][10][16] 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.[9]
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.[17] 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.[15]
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.[18]
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.[19]
^Bensen, Jeannette T.; Dawson, Paul A.; Mychaleckyj, Josyf C.; Bowden, Donald W. (November 2001). "Identification of a Novel Human Cytokine Gene in the Interleukin Gene Cluster on Chromosome 2q12-14". Journal of Interferon & Cytokine Research. 21 (11): 899–904.
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^Hessam, S.; Sand, M.; Gambichler, T.; Skrygan, M.; Rüddel, I.; Bechara, F.G. (2018). "Interleukin‐36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop". British Journal of Dermatology. 178 (3): 761–767.
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^Guo, Z. S.; Li, C.; Lin, Z. M.; Huang, J. X.; Wei, Q. J.; Wang, X. W.; Xie, Y. Y.; Liao, Z. T.; Chao, S. Y.; Gu, J. R. (February 2010). "Association of IL-1 gene complex members with ankylosing spondylitis in Chinese Han population". International Journal of Immunogenetics. 37 (1): 33–37.
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^Monnet, Dominique; Kadi, Amir; Izac, Brigitte; Lebrun, Nicolas; Letourneur, Franck; Zinovieva, Elena; Said-Nahal, Roula; Chiocchia, Gilles; Breban, Maxime (2012-02-06). "Association between the IL-1 family gene cluster and spondyloarthritis". Annals of the Rheumatic Diseases. 71 (6): 885–890.
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^Jung, MY; Kang, SW; Kim, SK; Kim, H-J; Yun, DH; Yim, S-V; Hong, SJ; Chung, J-H (2010-02-09). "The interleukin-1 family gene polymorphisms in Korean patients with rheumatoid arthritis". Scandinavian Journal of Rheumatology. 39 (3): 190–196.
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abRudloff, Ina; Godsell, Jack; Nold-Petry, Claudia A.; Harris, James; Hoi, Alberta; Morand, Eric F.; Nold, Marcel F. (2015-11-25). "Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus". Arthritis & Rheumatology. 67 (12): 3219–3225.
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^Yuan, X. L.; Li, Y.; Pan, X. H.; Zhou, M.; Gao, Q. Y.; Li, M. C. (May 2016). "Production of recombinant human interleukin-38 and its inhibitory effect on the expression of proinflammatory cytokines in THP-1 cells". Molecular Biology. 50 (3): 405–411.
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^Chu, Man; Tam, Lai Shan; Zhu, Jing; Jiao, Delong; Liu, De Hua; Cai, Zhe; Dong, Jie; Kai Lam, Christopher Wei; Wong, Chun Kwok (March 2017). "In vivo anti-inflammatory activities of novel cytokine IL-38 in Murphy Roths Large (MRL)/lpr mice". Immunobiology. 222 (3): 483–493.
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