title: IL-17 suppresses TNF-alpha-induced CCL27 production through induction of COX-2 in human keratinocytes.
abstract: BACKGROUND
  The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is dependent on nuclear factor kappaB (NF-kappaB) 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-kappaB 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-kappaB 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 E(2) 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-alpha induced dual phosphorylation of p38 MAPK and ERK.
  
  
  CONCLUSIONS
  IL-17 might suppress TNF-alpha-induced CCL27 production by inhibiting NF-kappaB 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.
authors.affiliation: Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Satsuki
authors.initials: S
authors.lastname: Koike
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D002478:Cells, Cultured; D054425:Chemokine CCL27; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C492276:CCL27 protein, human; D054425:Chemokine CCL27; D019742:Chemokines, CC; D020381:Interleukin-17; D011994:Recombinant Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D015232:Dinoprostone