IkBζ is a Key Regulator of Tumour Necrosis Factor-a and Interleukin-17A-mediated Induction of Interleukin-36g in Human Keratinocytes
DOI:
https://doi.org/10.2340/00015555-3749Keywords:
psoriasis, IL-36, IκBζ, keratinocytes, IL-17AAbstract
The interleukin (IL)-36 cytokine family plays an essential role in inflammatory processes in the skin and is implicated in the pathogenesis of psoriasis. This study explored the role of IL-36 in psoriasis and investigated the molecular mechanism involved in tumour necrosis factor-α (TNFα)/IL-17A-mediated IL-36 induction. In human keratinocytes IL-36 expression was strongly upregulated by combined TNFα and IL-17A stimulation. Moreover, IκBζ, encoded by NFKBIZ, was identified as a key regulator required for TNFα/IL-17A-induced IL-36γ expression. TNFα/IL-17A-induced IL-36γ expression also involved the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase and ERK1/2 signalling pathways. Furthermore, a specific NF-κB DNA-binding site in the promoter region of IL36G responsible for the TNFα/IL-17A-induced IL36G gene expression was identified. Finally, in a cohort of patients with psoriasis receiving anti-IL-17A treatment, a positive correlation was found between the expression of NFKBIZ and IL36G. In conclusion, these data reveal a novel crucial regulatory mechanism by which TNFα and IL-17A regulate IL-36γ expression.
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Gresnigt MS, van de Veerdonk FL. Biology of IL-36 cytokines and their role in disease. Semin Immunol 2013; 25: 458-465.
DOI: https://doi.org/10.1016/j.smim.2013.11.003
Dunn E, Sims JE, Nicklin MJ, O'Neill LA. Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol 2001; 22: 533-536.
DOI: https://doi.org/10.1016/S1471-4906(01)02034-8
Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem 2004; 279: 13677-13688.
DOI: https://doi.org/10.1074/jbc.M400117200
Gabay C, Towne JE. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J Leukoc Biol 2015; 97: 645-652.
DOI: https://doi.org/10.1189/jlb.3RI1014-495R
Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, et al. Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. J Biol Chem 2011; 286: 42594-42602.
DOI: https://doi.org/10.1074/jbc.M111.267922
Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432-437.
DOI: https://doi.org/10.1016/j.ajhg.2011.07.022
Chu M, Wong CK, Cai Z, Dong J, Jiao D, Kam NW, et al. Elevated expression and pro-inflammatory activity of IL-36 in patients with systemic lupus erythematosus. Molecules 2015; 20: 19588-19604.
DOI: https://doi.org/10.3390/molecules201019588
Boutet MA, Bart G, Penhoat M, Amiaud J, Brulin B, Charrier C, et al. Distinct expression of interleukin (IL)-36alpha, beta and gamma, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease. Clin Exp Immunol 2016; 184: 159-173.
DOI: https://doi.org/10.1111/cei.12761
Di Meglio P, Villanova F, Nestle FO. Psoriasis. Cold Spring Harb Perspect Med 2014; 4: a015354.
DOI: https://doi.org/10.1101/cshperspect.a015354
Carrier Y, Ma HL, Ramon HE, Napierata L, Small C, O'Toole M, et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol 2011; 131: 2428-2437.
DOI: https://doi.org/10.1038/jid.2011.234
Keermann M, Koks S, Reimann E, Abram K, Erm T, Silm H, et al. Expression of IL-36 family cytokines and IL-37 but not IL-38 is altered in psoriatic skin. J Dermatol Sci 2015; 80: 150-152.
DOI: https://doi.org/10.1016/j.jdermsci.2015.08.002
Traks T, Keermann M, Prans E, Karelson M, Loite U, Koks G, et al. Polymorphisms in IL36G gene are associated with plaque psoriasis. BMC Med Genet 2019; 20: 10.
DOI: https://doi.org/10.1186/s12881-018-0742-2
Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, et al. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med 2007; 204: 2603-2614.
DOI: https://doi.org/10.1084/jem.20070157
Mahil SK, Catapano M, Di Meglio P, Dand N, Ahlfors H, Carr IM, et al. An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target. Sci Transl Med 2017; 9: eaan2514.
DOI: https://doi.org/10.1126/scitranslmed.aan2514
Bertelsen T, Ljungberg C, Litman T, Huppertz C, Hennze R, Rønholt K, et al. I?B? is a key player in the antipsoriatic effects of secukinumab. J Allergy Clin Immunol 2020; 145: 379-390.
DOI: https://doi.org/10.1016/j.jaci.2019.09.029
Johansen C. Generation and culturing of primary human keratinocytes from adult skin. J Vis Exp 2017; 130: 56863.
DOI: https://doi.org/10.3791/56863
Bachmann M, Scheiermann P, Hardle L, Pfeilschifter J, Muhl H. IL-36gamma/IL-1F9, an innate T-bet target in myeloid cells. J Biol Chem 2012; 287: 41684-41696.
DOI: https://doi.org/10.1074/jbc.M112.385443
Johansen C, Iversen L, Ryborg A, Kragballe K. 1alpha,25-dihydroxyvitamin D3 induced differentiation of cultured human keratinocytes is accompanied by a PKC-independent regulation of AP-1 DNA binding activity. J Invest Dermatol 2000; 114: 1174-1179.
DOI: https://doi.org/10.1046/j.1523-1747.2000.00003.x
Johnston A, Xing X, Guzman AM, Riblett M, Loyd CM, Ward NL, et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. J Immunol 2011; 186: 2613-2622.
DOI: https://doi.org/10.4049/jimmunol.1003162
Johansen C, Bertelsen T, Ljungberg C, Mose M, Iversen L. Characterization of TNF-alpha- and IL-17A-mediated synergistic induction of DEFB4 gene expression in human keratinocytes through I?B?. J Invest Dermatol 2016; 136: 1608-1616.
DOI: https://doi.org/10.1016/j.jid.2016.04.012
Gabr MA, Jing L, Helbling AR, Sinclair SM, Allen KD, Shamji MF, et al. Interleukin-17 synergizes with IFNgamma or TNFalpha to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells. J Orthop Res 2011; 29: 1-7.
DOI: https://doi.org/10.1002/jor.21206
Goldberg M, Nadiv O, Luknar-Gabor N, Agar G, Beer Y, Katz Y. Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes. Mol Immunol 2009; 46: 1854-1859.
DOI: https://doi.org/10.1016/j.molimm.2009.01.004
Honda K, Wada H, Nakamura M, Nakamoto K, Inui T, Sada M, et al. IL-17A synergistically stimulates TNF-alpha-induced IL-8 production in human airway epithelial cells: a potential role in amplifying airway inflammation. Exp Lung Res 2016; 42: 205-216.
DOI: https://doi.org/10.1080/01902148.2016.1190796
Liu Y, Mei J, Gonzales L, Yang G, Dai N, Wang P, et al. IL-17A and TNF-alpha exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol 2011; 186: 3197-3205.
DOI: https://doi.org/10.4049/jimmunol.1002016
Nonaka M, Ogihara N, Fukumoto A, Sakanushi A, Kusama K, Pawankar R, et al. Synergistic induction of macrophage inflammatory protein-3alpha;/CCL20 production by interleukin-17A and tumor necrosis factor-alpha; in nasal polyp fibroblasts. World Allergy Organ J 2009; 2: 218-223.
DOI: https://doi.org/10.1097/WOX.0b013e3181bdd219
Shinjo T, Iwashita M, Yamashita A, Sano T, Tsuruta M, Matsunaga H, et al. IL-17A synergistically enhances TNFalpha-induced IL-6 and CCL20 production in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2016; 477: 241-246.
DOI: https://doi.org/10.1016/j.bbrc.2016.06.049
Johansen C, Mose M, Ommen P, Bertelsen T, Vinter H, Hailfinger S, et al. I?B? is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A 2015; 112: E5825-E5833.
DOI: https://doi.org/10.1073/pnas.1509971112
Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein I?B?. Nature 2004; 430: 218-222.
DOI: https://doi.org/10.1038/nature02738
Muller A, Hennig A, Lorscheid S, Grondona P, Schulze-Osthoff K, Hailfinger S, et al. IkappaBzeta is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes. Proc Natl Acad Sci U S A 2018; 115: 10088-10093.
DOI: https://doi.org/10.1073/pnas.1801377115
Pfaff CM, Marquardt Y, Fietkau K, Baron JM, Luscher B. The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Sci Rep 2017; 7: 15631.
DOI: https://doi.org/10.1038/s41598-017-15892-7
Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M, Nograles KE, Tian S, Cardinale I, et al. Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 2011; 131: 677-687.
DOI: https://doi.org/10.1038/jid.2010.340
Mercurio L, Morelli M, Scarponi C, Eisenmesser EZ, Doti N, Pagnanelli G, et al. 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: 1104.
DOI: https://doi.org/10.1038/s41419-018-1143-3
Muromoto R, Hirao T, Tawa K, Hirashima K, Kon S, Kitai Y, et al. IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IkappaB-zeta in keratinocytes. Int Immunol 2016; 28: 443-452.
DOI: https://doi.org/10.1093/intimm/dxw011
Takahashi K, Nishida A, Shioya M, Imaeda H, Bamba S, Inatomi O, et al. Interleukin (IL)-1? Is a Strong Inducer of IL-36? expression in human colonic myofibroblasts. PloS One 2015; 10: e0138423.
DOI: https://doi.org/10.1371/journal.pone.0138423
Johansen C, E. Flindt, K. Kragballe, J. Henningsen, M. Westergaard, K. Kristiansen, L. Iversen. Inverse regulation of the nuclear factor-kB binding to the p53 and interleukin-8 kB response elements in lesional psoriatic skin. J Invest Dermatol 2005; 124: 1284-1292.
DOI: https://doi.org/10.1111/j.0022-202X.2005.23749.x
Johansen C, Kragballe K, Westergaard M, Henningsen J, Kristiansen K, Iversen L. The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin. Br J Dermatol 2005; 152: 37-42.
DOI: https://doi.org/10.1111/j.1365-2133.2004.06304.x
Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, et al. Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol 2005; 124: 1275-1283.
DOI: https://doi.org/10.1111/j.0022-202X.2005.23735.x
D'Erme AM, Wilsmann-Theis D, Wagenpfeil J, Holzel M, Ferring-Schmitt S, Sternberg S, et al. IL-36gamma (IL-1F9) is a biomarker for psoriasis skin lesions. J Invest Dermatol 2015; 135: 1025-1032.
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