title: 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity.
abstract: 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid (12- HHT) is an enzymatic product of prostaglandin H(2) (PGH(2)) derived from cyclooxygenase (COX)-mediated arachidonic acid metabolism. Despite the high level of 12-HHT present in tissues and bodily fluids, its precise function remains largely unknown. In this study, we found that 12-HHT treatment in HaCaT cells remarkably down-regulated the ultraviolet B (UVB) irradiation-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation. In an approach to identify the down-stream signaling mechanism by which 12-HHT down-regulates UVB-induced IL-6 synthesis in keratinocytes, we observed that 12-HHT inhibits the UVB-stimulated activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). In addition, we found that 12-HHT markedly up-regulates MAPK phosphatase-1 (MKP-1), a critical negative regulator of p38 MAPK. When MKP-1 was suppressed by siRNA knock-down, the 12-HHT-mediated inhibitory effects on the UVB-stimulated activation of p38 MAPK and NF-κB, as well as the production of IL-6, were attenuated in HaCaT cells. Taken together, our results suggest that 12-HHT exerts anti-inflammatory effect via up-regulation of MKP-1, which negatively regulates p38 MAPK and NF-κB, thus attenuating IL-6 production in UVB-irradiated HaCaT cells. Considering the critical role of IL-6 in cutaneous inflammation, our findings provide the basis for the application of 12-HHT as a potential anti-inflammatory therapeutic agent in UV-induced skin diseases.
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Jin-Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Ho-Cheol
authors.initials: HC
authors.lastname: Ryu
authors.forename: Yee Ching
authors.initials: YC
authors.lastname: Ng
authors.forename: Cheolmin
authors.initials: C
authors.lastname: Kim
authors.forename: Jun-Dong
authors.initials: JD
authors.lastname: Wei
authors.forename: Vikineswary
authors.initials: V
authors.lastname: Sabaratnam
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D018102:Receptors, Leukotriene B4 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012871:Skin Diseases / Q000188:drug therapy; D014466:Ultraviolet Rays; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005231:Fatty Acids, Unsaturated; D015850:Interleukin-6; C485878:LTB4R2 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018102:Receptors, Leukotriene B4; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1