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In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH<jats:sub>2<\/jats:sub>, at 100 \u03bcM was significantly reduced by TET, DOX, or MIN at 5 and 10 \u03bcM, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-\u03b1)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH<jats:sub>2<\/jats:sub>, and that synergistic increase in the production of IL-8 was suppressed by 100 nM<jats:italic>PAR2<\/jats:italic>-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 \u03bcM. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.<\/jats:p>","DOI":"10.1128\/aac.01540-08","type":"journal-article","created":{"date-parts":[[2009,3,3]],"date-time":"2009-03-03T02:54:31Z","timestamp":1236048871000},"page":"1760-1765","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":54,"title":["Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocytes"],"prefix":"10.1128","volume":"53","author":[{"given":"Chika","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroe","family":"Konishi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyofumi","family":"Yamanishi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl224"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"14014","DOI":"10.1073\/pnas.93.24.14014","volume":"93","year":"1996","unstructured":"Amin, A. 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