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IL-36: An Epithelial Cytokine Important in Psoriasis

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Abstract

Interleukin-36 (IL-36) refers to three cytokines that are members of the IL-1 family. These cytokines are expressed predominantly but not exclusively by epithelial tissues. Similar to other IL-1 family cytokines, they promote inflammatory responses by activating kinases such as JNK, p38, and the IKKs, and activating transcription factors such as NFκB. They only do this, however, after N-terminal processing, which increases their specific activity by three to five orders of magnitude. Extensive evidence links IL-36 to various forms of psoriasis. It is also very likely involved in lung physiology and pathology and may play a role in the biology of other tissues including kidney, joint, and adipose tissue. In part, these activities take place by direct action of IL-36 on tissue cells. In part, however, they are undoubtedly mediated by the action of IL-36 on cells of the immune system, which results in responses marked by production of IFN-γ. Although we are learning much about the role of IL-36 in different tissues, it is clear that we are at a very early stage in understanding the biology of this cytokine.

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References

  • Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8(9):942–949

    Article  PubMed  CAS  Google Scholar 

  • Akira S (2000) The role of IL-18 in innate immunity. Curr Opin Immunol 12(1):59–63

    Article  PubMed  CAS  Google Scholar 

  • Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360(23):2426–2437

    Article  PubMed  CAS  Google Scholar 

  • Ali S, Huber M, Kollewe C, Bischoff SC, Falk W, Martin MU (2007) IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc Natl Acad Sci USA 104(47):18660–18665

    Article  PubMed  CAS  Google Scholar 

  • Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, Kanaly ST, Towne JE, Willis CR, Kuechle MK, Sims JE, Peschon JJ (2007) Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med 204(11):2603–2614

    Article  PubMed  CAS  Google Scholar 

  • Blumberg H, Dinh H, Dean C Jr, Trueblood ES, Bailey K, Shows D, Bhagavathula N, Aslam MN, Varani J, Towne JE, Sims JE (2010) IL-1RL2 and its ligands contribute to the cytokine network in psoriasis. J Immunol 185(7):4354–4362

    Article  PubMed  CAS  Google Scholar 

  • Bochkov YA, Hanson KM, Keles S, Brockman-Schneider RA, Jarjour NN, Gern JE (2010) Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma. Mucosal Immunol 3(1):69–80

    Article  PubMed  CAS  Google Scholar 

  • Carrier Y, Ma HL, Ramon HE, Napierata L, Small C, O’Toole M, Young DA, Fouser LA, Nickerson-Nutter C, Collins M, Dunussi-Joannopoulos K, Medley QG (2011) Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol 131(12):2428–2437

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Wang Y, Bai C, Wang X (2012) Alterations of plasma inflammatory biomarkers in the healthy and chronic obstructive pulmonary disease patients with or without acute exacerbation. J Proteomics 75(10):2835–2843

    Article  PubMed  CAS  Google Scholar 

  • Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30(4):576–587

    Article  PubMed  CAS  Google Scholar 

  • Chustz RT, Nagarkar DR, Poposki JA, Favoreto S Jr, Avila PC, Schleimer RP, Kato A (2011) Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells. Am J Respir Cell Mol Biol 45(1):145–153

    Article  PubMed  CAS  Google Scholar 

  • Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA (2001) Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol 167(3):1440–1446

    PubMed  CAS  Google Scholar 

  • DeVoti JA, Rosenthal DW, Wu R, Abramson AL, Steinberg BM, Bonagura VR (2008) Immune dysregulation and tumor-associated gene changes in recurrent respiratory papillomatosis: a paired microarray analysis. Mol Med 14(9–10):608–617

    PubMed  CAS  Google Scholar 

  • Dinarello CA (1999) IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 103(1 Pt 1):11–24

    Article  PubMed  CAS  Google Scholar 

  • Dinarello C, Arend W, Sims J, Smith D, Blumberg H, O’Neill L, Goldbach-Mansky R, Pizarro T, Hoffman H, Bufler P, Nold M, Ghezzi P, Mantovani A, Garlanda C, Boraschi D, Rubartelli A, Netea M, van der Meer J, Joosten L, Mandrup-Poulsen T, Donath M, Lewis E, Pfeilschifter J, Martin M, Kracht M, Muehl H, Novick D, Lukic M, Conti B, Solinger A, Peyman K, van de Veerdonk F, Gabel C (2010) IL-1 family nomenclature. Nat Immunol 11(11):973

    Article  PubMed  CAS  Google Scholar 

  • Ewart SL, Kuperman D, Schadt E, Tankersley C, Grupe A, Shubitowski DM, Peltz G, Wills-Karp M (2000) Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol 23(4):537–545

    Article  PubMed  CAS  Google Scholar 

  • Farooq M, Nakai H, Fujimoto A, Fujikawa H, Matsuyama A, Kariya N, Aizawa A, Fujiwara H, Ito M, Shimomura Y (2013) Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 34(1):176–183

    Article  PubMed  CAS  Google Scholar 

  • Goldbach-Mansky R (2012) Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 167(3):391–404

    Article  PubMed  CAS  Google Scholar 

  • Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K, Paul W (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA 106(32):13463–13468

    Article  PubMed  CAS  Google Scholar 

  • Ichii O, Otsuka S, Sasaki N, Yabuki A, Ohta H, Takiguchi M, Hashimoto Y, Endoh D, Kon Y (2010) Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions. Lab Invest 90(3):459–475

    Article  PubMed  CAS  Google Scholar 

  • Johnson-Huang LM, Lowes MA, Krueger JG (2012) Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech 5(4):423–433

    Article  PubMed  CAS  Google Scholar 

  • Johnston A, Xing X, Guzman AM, Riblett M, Loyd CM, Ward NL, Wohn C, Prens EP, Wang F, Maier LE, Kang S, Voorhees JJ, Elder JT, Gudjonsson JE (2011) 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 186(4):2613–2622

    Article  PubMed  CAS  Google Scholar 

  • Kryczek I, Wei S, Vatan L, Escara-Wilke J, Szeliga W, Keller ET, Zou W (2007) Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J Immunol 179(3):1423–1426

    PubMed  CAS  Google Scholar 

  • Lasiglie D, Traggiai E, Federici S, Alessio M, Buoncompagni A, Accogli A, Chiesa S, Penco F, Martini A, Gattorno M (2011) Role of IL-1 beta in the development of human T(H)17 cells: lesson from NLPR3 mutated patients. PLoS One 6(5):e20014

    Article  PubMed  CAS  Google Scholar 

  • Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366(13):1190–1199

    Article  PubMed  CAS  Google Scholar 

  • Li M, Lu Z, Cheng R, Li H, Guo Y, Yao Z (2013) IL36RN gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients. Br J Dermatol 168(2):452–455

    Article  PubMed  CAS  Google Scholar 

  • Lovenberg TW, Crowe PD, Liu C, Chalmers DT, Liu XJ, Liaw C, Clevenger W, Oltersdorf T, De Souza EB, Maki RA (1996) Cloning of a cDNA encoding a novel interleukin-1 receptor related protein (IL 1R-rp2). J Neuroimmunol 70(2):113–122

    Article  PubMed  CAS  Google Scholar 

  • Magne D, Palmer G, Barton JL, Mezin F, Talabot-Ayer D, Bas S, Duffy T, Noger M, Guerne PA, Nicklin MJ, Gabay C (2006) The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes. Arthritis Res Ther 8(3):R80

    Article  PubMed  Google Scholar 

  • Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, Zribi J, Bal E, Cluzeau C, Chrabieh M, Towne JE, Douangpanya J, Pons C, Mansour S, Serre V, Makni H, Mahfoudh N, Fakhfakh F, Bodemer C, Feingold J, Hadj-Rabia S, Favre M, Genin E, Sahbatou M, Munnich A, Casanova JL, Sims JE, Turki H, Bachelez H, Smahi A (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 365(7):620–628

    Article  PubMed  CAS  Google Scholar 

  • Martin U, Scholler J, Gurgel J, Renshaw B, Sims JE, Gabel CA (2009) Externalization of the leaderless cytokine IL-1F6 occurs in response to lipopolysaccharide/ATP activation of transduced bone marrow macrophages. J Immunol 183(6):4021–4030

    Article  PubMed  CAS  Google Scholar 

  • Mutamba S, Allison A, Mahida Y, Barrow P, Foster N (2012) Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9. Eur J Immunol 42(3):607–617

    Article  PubMed  CAS  Google Scholar 

  • Naldi L, Gambini D (2007) The clinical spectrum of psoriasis. Clin Dermatol 25(6):510–518

    Article  PubMed  Google Scholar 

  • Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361(5):496–509

    Article  PubMed  CAS  Google Scholar 

  • Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K (2002) A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 79(5):718–725

    Article  PubMed  CAS  Google Scholar 

  • Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, Knight J, Spain SL, Nestle FO, Burden AD, Capon F, Trembath RC, Barker JN (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 89(3):432–437

    Article  PubMed  CAS  Google Scholar 

  • Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM (2012) Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 12(8):570–580

    Article  PubMed  CAS  Google Scholar 

  • Parsanejad R, Fields WR, Steichen TJ, Bombick BR, Doolittle DJ (2008) Distinct regulatory profiles of interleukins and chemokines in response to cigarette smoke condensate in normal human bronchial epithelial (NHBE) cells. J Interferon Cytokine Res 28(12):703–712

    Article  PubMed  CAS  Google Scholar 

  • Ramadas RA, Li X, Shubitowski DM, Samineni S, Wills-Karp M, Ewart SL (2006) IL-1 Receptor antagonist as a positional candidate gene in a murine model of allergic asthma. Immunogenetics 58(10):851–855

    Article  PubMed  CAS  Google Scholar 

  • Ramadas RA, Ewart SL, Medoff BD, Levine AM (2011) Interleukin-1 family member 9 stimulates chemokine production and neutrophil influx in mouse lungs. Am J Respir Cell Mol Biol 44(2):134–145

    Article  PubMed  CAS  Google Scholar 

  • Ramadas RA, Ewart SL, Iwakura Y, Medoff BD, Levine AM (2012) IL-36alpha exerts pro-inflammatory effects in the lungs of mice. PLoS One 7(9):e45784

    Article  PubMed  CAS  Google Scholar 

  • Rao DA, Tracey KJ, Pober JS (2007) IL-1alpha and IL-1beta are endogenous mediators linking cell injury to the adaptive alloimmune response. J Immunol 179(10):6536–6546

    PubMed  CAS  Google Scholar 

  • Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, Hessner MJ, Verbsky J (2009) An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 360(23):2438–2444

    Article  PubMed  CAS  Google Scholar 

  • Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490

    Article  PubMed  CAS  Google Scholar 

  • Sims JE (2002) IL-1 and IL-18 receptors, and their extended family. Curr Opin Immunol 14(1):117–122

    Article  PubMed  CAS  Google Scholar 

  • Sims JE, Nicklin MJ, Bazan JF, Barton JL, Barfield SJ, Ford JE, Kastelein RA, Kumar S, Liu H, Mulero JJ, Pan J, Pan Y, Smith DE, Young PR (2001) A new nomenclature for IL-1-famuly genes. Trends Immunol 22(10):536–537

    Google Scholar 

  • Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10(2):89–102

    Article  PubMed  CAS  Google Scholar 

  • Sims JE, Painter SL, Gow IR (1995) Genomic organization of the type I and type II IL-1 receptors. Cytokine 7(6):483–490

    Article  PubMed  CAS  Google Scholar 

  • Sugiura K, Takeichi T, Kono M, Ogawa Y, Shimoyama Y, Muro Y, Akiyama M (2012) A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. Br J Dermatol 167(3):699–701

    Article  PubMed  CAS  Google Scholar 

  • Taylor SL, Renshaw BR, Garka KE, Smith DE, Sims JE (2002) Genomic organization of the interleukin-1 locus. Genomics 79(5):726–733

    Article  PubMed  CAS  Google Scholar 

  • Tortola L, Rosenwald E, Abel B, Blumberg H, Schafer M, Coyle AJ, Renauld JC, Werner S, Kisielow J, Kopf M (2012) Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest 122(11):3965–3976

    Article  PubMed  CAS  Google Scholar 

  • Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE (2004) 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 279(14):13677–13688

    Article  PubMed  CAS  Google Scholar 

  • Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE (2011) 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 286(49):42594–42602

    Article  PubMed  CAS  Google Scholar 

  • Trajkovic V, Sweet MJ, Xu D (2004) T1/ST2–an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev 15(2–3):87–95

    Article  PubMed  CAS  Google Scholar 

  • van Asseldonk EJ, Stienstra R, Koenen TB, van Tits LJ, Joosten LA, Tack CJ, Netea MG (2010) The effect of the interleukin-1 cytokine family members IL-1F6 and IL-1F8 on adipocyte differentiation. Obesity (Silver Spring) 18(11):2234–2236

    Article  Google Scholar 

  • Vigne S, Palmer G, Lamacchia C, Martin P, Talabot-Ayer D, Rodriguez E, Ronchi F, Sallusto F, Dinh H, Sims JE, Gabay C (2011) IL-36R ligands are potent regulators of dendritic and T cells. Blood 118(22):5813–5823

    Article  PubMed  CAS  Google Scholar 

  • Vigne S, Palmer G, Martin P, Lamacchia C, Strebel D, Rodriguez E, Olleros ML, Vesin D, Garcia I, Ronchi F, Sallusto F, Sims JE, Gabay C (2012) IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells. Blood 120(17):3478–3487

    Article  PubMed  CAS  Google Scholar 

  • Vos JB, van Sterkenburg MA, Rabe KF, Schalkwijk J, Hiemstra PS, Datson NA (2005) Transcriptional response of bronchial epithelial cells to Pseudomonas aeruginosa: identification of early mediators of host defense. Physiol Genomics 21(3):324–336

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Krueger JG, Kao MC, Lee E, Du F, Menter A, Wong WH, Bowcock AM (2003) Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 13(1):69–78

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Immunology, 4207 43rd Avenue NE, Seattle, WA, 98105, USA

    John E. Sims

  2. Department of Pathology and Immunology, CMU/Rue Michel-Servet 1, 1211, Geneva, Switzerland

    Solenne Vigne & Cem Gabay

  3. Amgen, 1201 Amgen Place W, Seattle, WA, 98119, USA

    Jennifer E. Towne

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  1. John E. Sims
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  2. Solenne Vigne
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  3. Cem Gabay
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  4. Jennifer E. Towne
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Correspondence to John E. Sims .

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Editors and Affiliations

  1. Department of Immunoregulation Institute of Medical Science, Tokyo Medical University, Tokyo, Tokyo, Japan

    Takayuki Yoshimoto

  2. Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Tomohiro Yoshimoto

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Sims, J.E., Vigne, S., Gabay, C., Towne, J.E. (2014). IL-36: An Epithelial Cytokine Important in Psoriasis. In: Yoshimoto, T., Yoshimoto, T. (eds) Cytokine Frontiers. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54442-5_8

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