Interleukin-38 and Insulin Resistance

Kamil      Klejbuk; Marek      Strączkowski

doi:10.2174/1871530323666230911114150

Abstract

Insulin resistance, i.e., decreased biological response to insulin, is a risk factor for many diseases, such as obesity, type 2 diabetes (T2DM), cardiovascular disease, polycystic ovary syndrome, some forms of cancer and neurodegenerative diseases. One of its main causes is chronic low-grade inflammation, mediated by the proinflammatory pathways, such as the c-Jun N-terminal kinase (JNK) pathway and the nuclear factor kappa B (NFκB) pathway. Interleukin (IL)-38 (IL-38) is a newly discovered cytokine that belongs to the IL-1 family. There are three hypothetical pathways through which IL-38 may bind to the specific receptors and inhibit their proinflammatory activity. Those pathways are associated with IL-36 receptor (IL-36R), IL-1 receptor accessory protein-like 1 (IL1RAPL1) and IL-1 receptor 1 (IL1R1). There are studies linking IL-38 to improve insulin sensitivity through the difference in serum IL-38 in patients with insulin resistance or the correlation of IL-38 concentrations with insulin resistance indexes. However, many questions still remain regarding the biological activity of IL-38 itself and its role in the pathogenesis of insulin resistance. The goal of this study is to showcase IL-38, its biological activity, hypothesized signaling pathways, connection with insulin resistance and future perspectives of research on IL-38. We present that IL-38 associated signaling can be a potential target for the treatment of insulin resistance and associated diseases.

[1]
Abid, S.M.; Alaaraji, S.F.; Alrawi, K.F. Study of interleukins 13, 18, 27, 32 and 38 levels in Iraqi type 2 diabetes with insulin resistance. J. Educ. Sci. Stud.,  2019, 4, 14.

[2]
Kahn, S.E.; Hull, R.L.; Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature,  2006, 444(7121), 840-846.
 [http://dx.doi.org/10.1038/nature05482] [PMID: 17167471]

[3]
Ormazabal, V.; Nair, S.; Elfeky, O.; Aguayo, C.; Salomon, C.; Zuñiga, F.A. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc. Diabetol.,  2018, 17(1), 122.
 [http://dx.doi.org/10.1186/s12933-018-0762-4] [PMID: 30170598]

[4]
Mu, N.; Zhu, Y.; Wang, Y.; Zhang, H.; Xue, F. Insulin resistance: A significant risk factor of endometrial cancer. Gynecol. Oncol.,  2012, 125(3), 751-757.
 [http://dx.doi.org/10.1016/j.ygyno.2012.03.032] [PMID: 22449736]

[5]
Nikolajuk, A.; Kowalska, I.; Karczewska-Kupczewska, M.; Adamska, A.; Otziomek, E.; Wolczynski, S.; Kinalska, I.; Gorska, M.; Straczkowski, M. Serum soluble glycoprotein 130 concentration is inversely related to insulin sensitivity in women with polycystic ovary syndrome. Diabetes,  2010, 59(4), 1026-1029.
 [http://dx.doi.org/10.2337/db09-1316] [PMID: 20103703]

[6]
Strączkowski, M.; Nikołajuk, A.; Majewski, R.; Filarski, R.; Stefanowicz, M.; Matulewicz, N.; Karczewska-Kupczewska, M. The effect of moderate weight loss, with or without (1, 3)(1, 6)-β-glucan addition, on subcutaneous adipose tissue inflammatory gene expression in young subjects with uncomplicated obesity. Endocrine,  2018, 61(2), 275-284.
 [http://dx.doi.org/10.1007/s12020-018-1619-z] [PMID: 29737494]

[7]
Fernández-Real, J.M.; Straczkowski, M.; Vendrell, J.; Soriguer, F.; Pérez del Pulgar, S.; Gallart, L.; López-Bermejo, A.; Kowalska, I.; Manco, M.; Cardona, F.; García-Gil, M.M.; Mingrone, G.; Richart, C.; Ricart, W.; Zorzano, A. Protection from inflammatory disease in insulin resistance: The role of mannan-binding lectin. Diabetologia,  2006, 49(10), 2402-2411.
 [http://dx.doi.org/10.1007/s00125-006-0381-6] [PMID: 16955210]

[8]
O’Reilly, E.L.; Eckersall, P.D. Acute phase proteins: A review of their function, behaviour and measurement in chickens. Worlds Poult. Sci. J.,  2014, 70(1), 27-44.
 [http://dx.doi.org/10.1017/S0043933914000038]

[9]
Catalan-Dibene, J.; McIntyre, L.L.; Zlotnik, A. Interleukin 30 to Interleukin 40. J. Interferon Cytokine Res.,  2018, 38(10), 423-439.
 [http://dx.doi.org/10.1089/jir.2018.0089] [PMID: 30328794]

[10]
Feng, J.; Lu, S.; Ou, B.; Liu, Q.; Dai, J.; Ji, C.; Zhou, H.; Huang, H.; Ma, Y. The role of JNk signaling pathway in obesity-driven insulin resistance. Diabetes Metab. Syndr. Obes.,  2020, 13, 1399-1406.
 [http://dx.doi.org/10.2147/DMSO.S236127] [PMID: 32425571]

[11]
Baker, R.G. Hayden, M.S.; Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab.,  2011, 13(1), 11-22.
 [http://dx.doi.org/10.1016/j.cmet.2010.12.008] [PMID: 21195345]

[12]
Ballak, D.B.; Stienstra, R.; Tack, C.J.; Dinarello, C.A.; Van Diepen, J.A. IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance. Cytokine,  2015, 75(2), 280-290.
 [http://dx.doi.org/10.1016/j.cyto.2015.05.005] [PMID: 26194067]

[13]
Lin, H.; Ho, A.S.; Haley-Vicente, D.; Zhang, J.; Bernal-Fussell, J.; Pace, A.M.; Hansen, D.; Schweighofer, K.; Mize, N.K.; Ford, J.E. Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J. Biol. Chem.,  2001, 276(23), 20597-20602.
 [http://dx.doi.org/10.1074/jbc.M010095200] [PMID: 11278614]

[14]
Xie, L.; Huang, Z.; Li, H.; Liu, X.; Zheng, S.; Su, W. IL-38: A new player in inflammatory autoimmune disorders. Biomolecules,  2019, 9(8), 345.
 [http://dx.doi.org/10.3390/biom9080345] [PMID: 31387327]

[15]
Bensen, J.T.; Dawson, P.A.; Mychaleckyj, J.C.; Bowden, D.W. Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2q12-14. J. Interferon Cytokine Res.,  2001, 21(11), 899-904.
 [http://dx.doi.org/10.1089/107999001753289505] [PMID: 11747621]

[16]
Yuan, X.; Peng, X.; Li, Y.; Li, M. Role of IL-38 and its related cytokines in inflammation. Mediators Inflamm.,  2015, 2015, 1-7.
 [http://dx.doi.org/10.1155/2015/807976] [PMID: 25873772]

[17]
de Graaf, D.M.; Maas, R.J.A.; Smeekens, S.P.; Eisenmesser, E.; Redzic, J.S.; Helsen, M.M.; Powers, N.E.; Li, S.; Kalabokis, V.; Gresnigt, M.S.; Joosten, L.A.B.; Dinarello, C.A.; van de Veerdonk, F.L. Human recombinant interleukin-38 suppresses inflammation in mouse models of local and systemic disease. Cytokine,  2021, 137, 155334.
 [http://dx.doi.org/10.1016/j.cyto.2020.155334] [PMID: 33128926]

[18]
Mora, J.; Schlemmer, A.; Wittig, I.; Richter, F.; Putyrski, M.; Frank, A.C.; Han, Y.; Jung, M.; Ernst, A.; Weigert, A.; Brüne, B. Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses. J. Mol. Cell Biol.,  2016, 8(5), 426-438.
 [http://dx.doi.org/10.1093/jmcb/mjw006] [PMID: 26892022]

[19]
Rudloff, I.; Godsell, J.; Nold-Petry, C.A.; Harris, J.; Hoi, A.; Morand, E.F.; Nold, M.F. Brief Report: Interleukin-38 exerts anti-inflammatory functions and is associated with disease activity in systemic lupus erythematosus. Arthritis Rheumatol.,  2015, 67(12), 3219-3225.
 [http://dx.doi.org/10.1002/art.39328] [PMID: 26314375]

[20]
Van de Veerdonk, F.L.; Stoeckman, A.K.; Wu, G.; Boeckermann, A.N.; Azam, T.; Netea, M.G.; Joosten, L.A.B.; Van der Meer, J.W.M.; Hao, R.; Kalabokis, V.; Dinarello, C.A. IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc. Natl. Acad. Sci. USA,  2012, 109(8), 3001-3005.
 [http://dx.doi.org/10.1073/pnas.1121534109] [PMID: 22315422]

[21]
Yuan, X.L.; Li, Y.; Pan, X.H.; Zhou, M.; Gao, Q.Y.; Li, M.C. [Production of recombinant human interleukin-38 and its inhibitory effect on the expression of proinflammatory cytokines in THP-1 cells]. Mol. Biol. (Mosk.),  2016, 50(3), 466-473.
 [http://dx.doi.org/10.7868/S0026898416030137] [PMID: 27414784]

[22]
Van de Veerdonk, F.L.; de Graaf, D.M.; Joosten, L.A.B.; Dinarello, C.A. Biology of IL-38 and its role in disease. Immunol. Rev.,  2018, 281(1), 191-196.
 [http://dx.doi.org/10.1111/imr.12612] [PMID: 29247986]

[23]
Gabay, C.; Towne, J.E. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J. Leukoc. Biol.,  2015, 97(4), 645-652.
 [http://dx.doi.org/10.1189/jlb.3RI1014-495R] [PMID: 25673295]

[24]
Boraschi, D.; Tagliabue, A. The interleukin-1 receptor family. Semin. Immunol.,  2013, 25(6), 394-407.
 [http://dx.doi.org/10.1016/j.smim.2013.10.023] [PMID: 24246227]

[25]
De Graaf, D.M.; Teufel, L.U.; Joosten, L.A.B.; Dinarello, C.A. Interleukin-38 in health and disease. Cytokine,  2022, 152, 155824.
 [http://dx.doi.org/10.1016/j.cyto.2022.155824] [PMID: 35220115]

[26]
Mantovani, A.; Dinarello, C.A.; Molgora, M.; Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity,  2019, 50(4), 778-795.
 [http://dx.doi.org/10.1016/j.immuni.2019.03.012] [PMID: 30995499]

[27]
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.; Gabay, C.; Palmer, G.; Le Goff, B.; Blanchard, F. Distinct expression of interleukin (IL)-36 α β and γ their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease. Clin. Exp. Immunol.,  2016, 184(2), 159-173.
 [http://dx.doi.org/10.1111/cei.12761] [PMID: 26701127]

[28]
Fonseca-Camarillo, G.; Furuzawa-Carballeda, J.; Iturriaga-Goyon, E.; Yamamoto-Furusho, J.K. Differential expression of IL-36 family members and IL-38 by immune and nonimmune cells in patients with active inflammatory bowel disease. BioMed Res. Int.,  2018, 2018, 1-12.
 [http://dx.doi.org/10.1155/2018/5140691] [PMID: 30643810]

[29]
Jiang, L.; Zhou, X.; Huang, C.; Bao, J.; Li, J.; Xu, K.; Dong, D.; Wu, L. The elevated expression of IL-38 serves as an anti-inflammatory factor in osteoarthritis and its protective effect in osteoarthritic chondrocytes. Int. Immunopharmacol.,  2021, 94, 107489.
 [http://dx.doi.org/10.1016/j.intimp.2021.107489] [PMID: 33774357]

[30]
Shi, L.; Ye, H.; Huang, J.; Li, Y.; Wang, X.; Xu, Z.; Chen, J.; Xiao, W.; Chen, R.; Yang, H. IL-38 exerts anti-inflammatory and antifibrotic effects in thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab.,  2021, 106(8), e3125-e3142.
 [http://dx.doi.org/10.1210/clinem/dgab154] [PMID: 33693700]

[31]
Tsilioni, I.; Pantazopoulos, H.; Conti, P.; Leeman, S.E.; Theoharides, T.C. IL-38 inhibits microglial inflammatory mediators and is decreased in amygdala of children with autism spectrum disorder. Proc. Natl. Acad. Sci. USA,  2020, 117(28), 16475-16480.
 [http://dx.doi.org/10.1073/pnas.2004666117] [PMID: 32601180]

[32]
Teufel, L.U.; de Graaf, D.M.; Netea, M.G.; Dinarello, C.A.; Joosten, L.A.B.; Arts, R.J.W. Circulating interleukin-38 concentrations in healthy adults. Front. Immunol.,  2022, 13, 964365.
 [http://dx.doi.org/10.3389/fimmu.2022.964365] [PMID: 36016926]

[33]
Chai, Y.; Lin, S.; Zhang, M.; Deng, L.; Chen, Y.; Xie, K.; Wang, C.; Xu, F. IL-38 is a biomarker for acute respiratory distress syndrome in humans and down-regulates Th17 differentiation in vivo. Clin. Immunol.,  2020, 210, 108315.
 [http://dx.doi.org/10.1016/j.clim.2019.108315] [PMID: 31756565]

[34]
Khattab, F.; Khater, E.; Ibraheem, H. Serum levels of interleukin-38 in sufferers with atopic eczema. J. Dermatol.,  2019, 39(2), 66.
 [http://dx.doi.org/10.4103/ejdv.ejdv_2_18]

[35]
Ali, Z.P.M.; Ghafouri-Fard, S.; Komaki, A.; Mazdeh, M.; Taheri, M.; Eftekharian, M.M. Assessment of IL-38 levels in patients with acquired immune-mediated polyneuropathies. J. Mol. Neurosci.,  2020, 70(9), 1385-1388.
 [http://dx.doi.org/10.1007/s12031-020-01558-z] [PMID: 32367504]

[36]
Xie, C.; Yan, W.; Quan, R.; Chen, C.; Tu, L.; Hou, X.; Fu, Y. Interleukin-38 is elevated in inflammatory bowel diseases and suppresses intestinal inflammation. Cytokine,  2020, 127, 154963.
 [http://dx.doi.org/10.1016/j.cyto.2019.154963] [PMID: 31927461]

[37]
Zhong, Y.; Yu, K.; Wang, X.; Wang, X.; Ji, Q.; Zeng, Q. Elevated plasma IL-38 concentrations in patients with acute ST-Segment elevation myocardial infarction and their dynamics after reperfusion treatment. Mediators Inflamm.,  2015, 2015, 1-10.
 [http://dx.doi.org/10.1155/2015/490120] [PMID: 26819499]

[38]
Xu, W.D.; Su, L.C.; He, C.S.; Huang, A.F. Plasma interleukin-38 in patients with rheumatoid arthritis. Int. Immunopharmacol.,  2018, 65, 1-7.
 [http://dx.doi.org/10.1016/j.intimp.2018.09.028] [PMID: 30268016]

[39]
Xu, F.; Lin, S.; Yan, X.; Wang, C.; Tu, H.; Yin, Y.; Cao, J. Interleukin 38 protects against lethal sepsis. J. Infect. Dis.,  2018, 218(7), 1175-1184.
 [http://dx.doi.org/10.1093/infdis/jiy289] [PMID: 29762676]

[40]
Mahmoud, M.R.E.S.; Adel, A.Z.M. Abd El- Fadeal, N.M.; Eyada, M.M.K. Interleukin 38 serum level is increased in patients with vitiligo, correlated with disease severity, and associated with signs of disease activity. J. Cosmet. Dermatol.,  2022, 21(8), 3515-3521.
 [http://dx.doi.org/10.1111/jocd.14612] [PMID: 34783147]

[41]
Hiz, P.; Kanbur, E.; Demir, N.; Akalin, H.; Cagan, E.; Pashazadeh, M.; Bal, S.H.; Tezcan, G.; Oral, H.B.; Budak, F. Roles of novel IL-1 family (IL-36, IL-37, and IL-38) members in chronic brucellosis. Cytokine,  2020, 135, 155211.
 [http://dx.doi.org/10.1016/j.cyto.2020.155211] [PMID: 32736334]

[42]
Mercurio, L.; Morelli, M.; Scarponi, C.; Eisenmesser, E.Z.; Doti, N.; Pagnanelli, G.; Gubinelli, E.; Mazzanti, C.; Cavani, A.; Ruvo, M.; Dinarello, C.A.; Albanesi, C.; Madonna, S. IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment. Cell Death Dis.,  2018, 9(11), 1104.
 [http://dx.doi.org/10.1038/s41419-018-1143-3] [PMID: 30377293]

[43]
Luo, D.; Chen, Y.; Zhou, N.; Li, T.; Wang, H. Blockade of Th17 response by IL-38 in primary Sjögren’s syndrome. Mol. Immunol.,  2020, 127, 107-111.
 [http://dx.doi.org/10.1016/j.molimm.2020.09.006] [PMID: 32950755]

[44]
Xu, J. Huang, G: Weng, L. Low serum interleukin-38 levels in patients with Graves’ disease and Hashimoto’s thyroiditis. J. Clin. Lab. Anal.,  2021, 36(1), e24101.

[45]
Diaz-Barreiro, A.; Huard, A.; Palmer, G. Multifaceted roles of IL-38 in inflammation and cancer. Cytokine,  2022, 151, 155808.
 [http://dx.doi.org/10.1016/j.cyto.2022.155808] [PMID: 35066449]

[46]
Sun, X.; Hou, T.; Cheung, E.; Iu, T.N.T.; Tam, V.W.H.; Chu, I.M.T.; Tsang, M.S.M.; Chan, P.K.S.; Lam, C.W.K.; Wong, C.K. Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma. Cell. Mol. Immunol.,  2020, 17(6), 631-646.
 [http://dx.doi.org/10.1038/s41423-019-0300-7] [PMID: 31645649]

[47]
Wei, Y.; Lan, Y.; Zhong, Y.; Yu, K.; Xu, W.; Zhu, R.; Sun, H.; Ding, Y.; Wang, Y.; Zeng, Q. Interleukin-38 alleviates cardiac remodelling after myocardial infarction. J. Cell. Mol. Med.,  2020, 24(1), 371-384.
 [http://dx.doi.org/10.1111/jcmm.14741] [PMID: 31746138]

[48]
Yuan, X.; Li, Y.; Pan, X.; Peng, X.; Song, G.; Jiang, W.; Gao, Q.; Li, M. IL-38 alleviates concanavalin A-induced liver injury in mice. Int. Immunopharmacol.,  2016, 40, 452-457.
 [http://dx.doi.org/10.1016/j.intimp.2016.09.023] [PMID: 27723569]

[49]
Cao, J.; Hua, L.; Zhang, S.; Tang, J.; Ke, F.; Wu, Z.; Xue, G. Serum interleukin-38 levels correlated with insulin resistance, liver injury and lipids in non-alcoholic fatty liver disease. Lipids Health Dis.,  2022, 21(1), 70.
 [http://dx.doi.org/10.1186/s12944-022-01676-0] [PMID: 35948957]

[50]
Li, Y.; Chen, S.; Sun, J.; Yu, Y.; Li, M. Interleukin‐38 inhibits adipogenesis and inflammatory cytokine production in 3T3‐L1 preadipocytes. Cell Biol. Int.,  2020, 44(11), 2357-2362.
 [http://dx.doi.org/10.1002/cbin.11428] [PMID: 32716099]

[51]
Xu, K.; Sun, J.; Chen, S.; Li, Y.; Peng, X.; Li, M.; Li, Y. Hydrodynamic delivery of IL-38 gene alleviates obesity-induced inflammation and insulin resistance. Biochem. Biophys. Res. Commun.,  2019, 508(1), 198-202.
 [http://dx.doi.org/10.1016/j.bbrc.2018.11.114] [PMID: 30477747]

[52]
Liu, Y.; Chen, T.; Zhou, F.; Mu, D.; Liu, S. Interleukin-38 increases the insulin sensitivity in children with the type 2 diabetes. Int. Immunopharmacol.,  2020, 82, 106264.
 [http://dx.doi.org/10.1016/j.intimp.2020.106264] [PMID: 32087495]

[53]
Yu, Z.; Liu, J.; Zhang, R.; Huang, X.; Sun, T.; Wu, Y.; Hambly, B.D.; Bao, S. IL-37 and 38 signalling in gestational diabetes. J. Reprod. Immunol.,  2017, 124, 8-14.
 [http://dx.doi.org/10.1016/j.jri.2017.09.011] [PMID: 28992508]

[54]
Gurău, F.; Silvestrini, A.; Matacchione, G.; Fazioli, F.; Bonfigli, A.R.; Olivieri, F.; Sabbatinelli, J. Plasma levels of interleukin-38 in healthy aging and in type 2 diabetes. Diabetes Res. Clin. Pract.,  2021, 171, 108585.
 [http://dx.doi.org/10.1016/j.diabres.2020.108585] [PMID: 33310128]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1871530323666230911114150	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873

Endocrine, Metabolic & Immune Disorders - Drug Targets

Interleukin-38 and Insulin Resistance

Abstract

Graphical Abstract

Endocrine, Metabolic & Immune Disorders - Drug Targets

Interleukin-38 and Insulin Resistance

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract