title: The inflammatory response of keratinocytes and its modulation by vitamin D: the role of MAPK signaling pathways.
abstract: The hormonal form of vitamin D, calcitriol, and its analogs are known for their beneficial effect in the treatment of inflammatory skin disorders. Keratinocytes play a role in epidermal inflammatory responses invoked by breeching of the epidermal barrier, by infectious agents and by infiltrating immune cells. We studied the role of calcitriol in the initiation of keratinocyte inflammatory response by the viral and injury mimic polyinosinic-polycytidylic acid (poly(I:C)) and in its maintenance by tumor-necrosis-factor α (TNFα) and investigated the role of the mitogen-activated protein kinase cascades in these processes and their regulation by calcitriol. The inflammatory response of human HaCaT keratinocytes to poly(I:C) or TNFα was assessed by measuring mRNA levels of 13 inflammation-related molecules by real-time PCR microarray and by in-depth investigation of the regulation of interleukin 8, intercellular-adhesion-molecule 1, and TNFα expression. We found that while calcitriol had only a minor effect on the keratinocyte response to poly(I:C) and a modest effect on the early response (2 h) to TNFα, it markedly attenuated the later response (16-24 h) to TNFα. The expression of CYP27B1, the enzyme responsible for calcitriol production, was marginally increased by poly(I:C) and markedly by TNFα treatment. This pattern suggests that while allowing the initial keratinocyte inflammatory response to proceed, calcitriol contributes to its timely resolution. Using pharmacological inhibitors we found that while the p38 MAPK and the extracellular signal-regulated kinase have only a minor role, c-Jun N-terminal kinase plays a pivotal role in the induction of the pro-inflammatory genes and its modulation by calcitriol.
authors.affiliation: Basil and Gerald Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Miodovnik
authors.forename: Ruth
authors.initials: R
authors.lastname: Koren
authors.forename: Esther
authors.initials: E
authors.lastname: Ziv
authors.forename: Amiram
authors.initials: A
authors.lastname: Ravid
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007369:Interferon Inducers / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology*; D046228:Microarray Analysis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007369:Interferon Inducers; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D014815:Vitamins; D018799:Intercellular Adhesion Molecule-1; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C