title: Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis.
abstract: Accumulating evidence indicates that IL-1 family members and Th17 cytokines have a pathogenic role in psoriasis. We investigated the regulatory interactions of the IL-1-like IL-36 cytokine family and the Th17 cytokines in the context of skin inflammation. We observed increased gene expression of all three IL-36 cytokines in a Th17-dominant psoriasis-like animal model. The induction was downregulated by neutralizing IL-22. Expression of the IL-36s was also induced in cultured primary human keratinocytes (KC) by IL-17A and tumor necrosis factor (TNF)-α, and IL-22 synergized with IL-17A and TNF-α. Furthermore, the IL-36s directly induced their own expression and the production of proinflammatory mediators (TNF-α, IL-6, IL-8) in KC. These functions were markedly enhanced with the addition of IL-17A or TNF-α to the cultures. Similarly, IL-36α and IL-36β augmented IL-17A-mediated induction of antibacterial peptides. Finally, we show that the increased gene expression of IL-36 correlated with Th17 cytokines in the lesions of psoriatic patients. Our results indicate that the IL-36 cytokines are not only regulated by Th17 cytokines, but that they themselves can regulate the expression and enhance the function of Th17 cytokines. We propose that a feedback loop between the IL-36 and Th17 cytokines is involved in driving cytokine expression in psoriatic tissues.
authors: Inflammation and Immunology, BioTherapeutic Research, Pfizer, Cambridge, Massachusetts 02140, USA.
authors: Yijun
authors: Y
authors: Carrier
authors: Hak-Ling
authors: HL
authors: Ma
authors: Hilda E
authors: HE
authors: Ramon
authors: Lee
authors: L
authors: Napierata
authors: Clayton
authors: C
authors: Small
authors: Margot
authors: M
authors: O'Toole
authors: Deborah A
authors: DA
authors: Young
authors: Lynette A
authors: LA
authors: Fouser
authors: Cheryl
authors: C
authors: Nickerson-Nutter
authors: Mary
authors: M
authors: Collins
authors: Kyri
authors: K
authors: Dunussi-Joannopoulos
authors: Quintus G
authors: QG
authors: Medley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011565:Psoriasis / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C502352:IL-1F8 protein, mouse; C569167:IL1F9 protein, mouse; C508586:IL36A protein, human; C508588:IL36B protein, human; C508589:IL36G protein, human; D007375:Interleukin-1; C543716:interleukin 1F6, mouse