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.[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 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.[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]

References

  1. ↑ Lin, Haishan; Ho, Alice S.; Haley-Vicente, Dana; Zhang, Jun; Bernal-Fussell, Juanita; Pace, Ann M.; Hansen, Derek; Schweighofer, Kathi; Mize, Nancy K.; Ford, John E. (2001-06-08). "Cloning and Characterization of IL-1HY2, a Novel Interleukin-1 Family Member". Journal of Biological Chemistry. 276 (23): 20597–20602. doi:10.1074/jbc.M010095200. ISSN 0021-9258. PMID 11278614.
  2. ↑ Mulero, Julio J.; Pace, Ann M.; Nelken, Sarah T.; Loeb, Deborah B.; Correa, Tanis R.; Drmanac, Radoje; Ford, John E. (1999). "IL1HY1: A Novel Interleukin-1 Receptor Antagonist Gene". Biochemical and Biophysical Research Communications. 263 (3): 702–706. doi:10.1006/bbrc.1999.1440. PMID 10512743.
  3. ↑ 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. doi:10.1089/107999001753289505. ISSN 1079-9907. PMID 11747621.
  4. ↑ Kumar, Sanjay; McDonnell, Peter C.; Lehr, Ruth; Tierney, Lauren; Tzimas, Maritsa N.; Griswold, Don E.; Capper, Elizabeth A.; Tal-Singer, Ruth; Wells, Grace I.; Doyle, Michael L.; Young, Peter R. (2000-04-07). "Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family". Journal of Biological Chemistry. 275 (14): 10308–10314. doi:10.1074/jbc.275.14.10308. ISSN 0021-9258. PMID 10744718.
  5. ↑ Chou, C‐T; Timms, A E; Wei, J C C; Tsai, W C; Wordsworth, B P; Brown, M A (August 2006). "Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese". Annals of the Rheumatic Diseases. 65 (8): 1106–1109. doi:10.1136/ard.2005.046847. ISSN 0003-4967. PMC 1798239. PMID 16361275.
  6. ↑ Zhong, Y.; Yu, K.; Wang, X.; Wang, X.; Ji, Q.; Zeng, Q. (2015). "Elevated Plasma IL-38 Concentrations in Patients with Acute ST-Segment Elevation Myocardial Infarction and Their Dynamics after Reperfusion Treatment". Mediators of Inflammation. 2015: 490120. doi:10.1155/2015/490120. PMC 4706979. PMID 26819499.
  7. ↑ Boutet, M.‐A.; Bart, G.; Penhoat, M.; Amiaud, J.; Brulin, B.; Charrier, C.; Morel, F.; Lecron, J.‐C.; Rolli‐Derkinderen, M.; Bourreille, A.; Vigne, S. (May 2016). "Distinct expression of interleukin (IL)‐36α, β and γ, their antagonist IL‐36Ra and IL‐38 in psoriasis, rheumatoid arthritis and Crohn's disease". Clinical and Experimental Immunology. 184 (2): 159–173. doi:10.1111/cei.12761. ISSN 0009-9104. PMC 4837235. PMID 26701127.
  8. ↑ 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. doi:10.1111/bjd.16019. PMID 28975626. S2CID 4442519.
  9. 1 2 3 4 Mora, Javier; Schlemmer, Andrea; Wittig, Ilka; Richter, Florian; Putyrski, Mateusz; Frank, Ann-Christin; Han, Yingying; Jung, Michaela; Ernst, Andreas; Weigert, Andreas; Brüne, Bernhard (2016-10-01). "Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses". Journal of Molecular Cell Biology. 8 (5): 426–438. doi:10.1093/jmcb/mjw006. ISSN 1674-2788. PMID 26892022.
  10. 1 2 van de Veerdonk, Frank L.; Stoeckman, Angela K.; Wu, Gouping; Boeckermann, Aaron N.; Azam, Tania; Netea, Mihai G.; Joosten, Leo A. B.; van der Meer, Jos W. M.; Hao, Ruyi; Kalabokis, Vassili; Dinarello, Charles A. (2012-02-21). "IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist". Proceedings of the National Academy of Sciences of the United States of America. 109 (8): 3001–3005. Bibcode:2012PNAS..109.3001V. doi:10.1073/pnas.1121534109. ISSN 0027-8424. PMC 3286950. PMID 22315422.
  11. ↑ 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. doi:10.1111/j.1744-313x.2009.00889.x. ISSN 1744-3121. PMID 19930406. S2CID 7176938.
  12. ↑ 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. doi:10.1136/annrheumdis-2011-200439. ISSN 0003-4967. PMID 22312160. S2CID 39081640.
  13. ↑ 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. doi:10.3109/03009740903447028. ISSN 0300-9742. PMID 20141484. S2CID 25725649.
  14. ↑ Russell, Aaron (2018-08-21). "Faculty of 1000 evaluation for Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits". doi:10.3410/f.726441711.793549745. S2CID 91368048. {{cite journal}}: Cite journal requires |journal= (help)
  15. 1 2 Rudloff, 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. doi:10.1002/art.39328. ISSN 2326-5191. PMID 26314375.
  16. ↑ 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. doi:10.1134/s0026893316030134. ISSN 0026-8933. PMID 27414784. S2CID 18254036.
  17. ↑ 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. doi:10.1016/j.imbio.2016.10.012. ISSN 0171-2985. PMID 27769564.
  18. ↑ Ciccia, F.; Accardo-Palumbo, A.; Alessandro, R.; Alessandri, C.; Priori, R.; Guggino, G.; Raimondo, S.; Carubbi, F.; Valesini, G.; Giacomelli, R.; Rizzo, A. (2015-06-03). "Interleukin-36α axis is modulated in patients with primary Sjögren's syndrome". Clinical & Experimental Immunology. 181 (2): 230–238. doi:10.1111/cei.12644. ISSN 0009-9104. PMC 4516438. PMID 25902739.
  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. doi:10.1136/annrheumdis-2016-210630. ISSN 0003-4967. PMID 28288964. S2CID 5466052.
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