Interleukin-38 Explained

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]

Discovery

IL-38 probably originated from a common ancestral gene - an ancient IL-1RN gene.[2] 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.[3] 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.[4] 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,[5] cardiovascular disease,[6] rheumatoid arthritis[7] or hidradenitis suppurativa.[8]

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.[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.

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 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.[15] There are also studies which show agonistic effect.[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.

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]

References

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  2. IL1HY1: A Novel Interleukin-1 Receptor Antagonist Gene. 1999 . 10.1006/bbrc.1999.1440 . Mulero . Julio J. . Pace . Ann M. . Nelken . Sarah T. . Loeb . Deborah B. . Correa . Tanis R. . Drmanac . Radoje . Ford . John E. . Biochemical and Biophysical Research Communications . 263 . 3 . 702–706 . 10512743 .
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  6. Elevated Plasma IL-38 Concentrations in Patients with Acute ST-Segment Elevation Myocardial Infarction and Their Dynamics after Reperfusion Treatment. 4706979. 2015. Zhong. Y.. Yu. K.. Wang. X.. Wang. X.. Ji. Q.. Zeng. Q.. Mediators of Inflammation. 2015. 490120. 26819499. 10.1155/2015/490120. free.
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  19. Boutet. Marie-Astrid. Najm. Aurélie. Bart. Géraldine. Brion. Régis. Touchais. Sophie. Trichet. Valérie. Layrolle. Pierre. Gabay. Cem. Palmer. Gaby. Blanchard. Frédéric. Le Goff. Benoit. 2017-03-13. IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro. Annals of the Rheumatic Diseases. 76. 7. 1304–1312. 10.1136/annrheumdis-2016-210630. 28288964. 5466052. 0003-4967.

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