IL-17 suppresses TNF-α-induced CCL27 production through induction of COX-2 in human keratinocytes

Background: The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is dependent on nuclear factor kappa B (NF-kappa B) activity and enhanced in lesions of patients with atopic dermatitis, psoriasis vulgaris, or allergic contact dermatitis. IL-17 is released from activated memory T cells and modulates skin inflammation. Objective: We examined the in vitro effects of IL-17 on TNF-alpha-induced CCL27 production in human keratinocytes. Methods: Keratinocytes were incubated with TNF-alpha, IL-17, or both. CCL27 secretion and mRNA levels were analyzed by means of ELISA and RT-PCR, respectively. COX-2 promoter and NF-kappa B activities were analyzed by using luciferase assays. COX-2 protein levels were analyzed by means of Western blotting. Results: IL-17 suppressed TNF-alpha-induced CCL27 secretion and mRNA expression and NF-kappa B activity in keratinocytes. The COX-2 inhibitor NS398 counteracted the effects of IL-17, and prostaglandin E-2 prevented counteraction by NS398. IL-17 alone or synergistically with TNF-alpha increased prostaglandin E2 release from keratinocytes, and the increase was suppressed by NS398. IL-17 alone or synergistically with TNF-alpha increased COX-2 mRNA and protein levels, promoter activity, and mRNA stability. The stimulatory effects of IL-17 on COX-2 expression were suppressed by inhibitors of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) kinase. IL-17 alone or synergistically with TNF-a induced dual phosphorylation of p38 MAPK and ERK. Conclusion: IL-17 might suppress TNF-alpha-induced CCL27 production by inhibiting NF-kappa B through induction of COX-2. The induction of COX-2 might be mediated by activation of p38 MAPK and ERK. T cell-derived IL-17 might alleviate T-cell skin infiltration through inhibition of CCL27 production.