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: Jin-Wook Lee, Ho-Cheol Ryu, Yee Ching Ng, Cheolmin Kim, Jun-Dong Wei, Vikineswary Sabaratnam, Jae-Hong Kim
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 44 Issue 6 Pg. 378-86 (Jun 30 2012) ISSN: 2092-6413 [Electronic] United States
• PMID: 22391335 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Fatty Acids, Unsaturated
• Interleukin-6
• LTB4R2 protein, human
• NF-kappa B
• RNA, Small Interfering
• Receptors, Leukotriene B4
• 12-hydroxy-5,8,10-heptadecatrienoic acid
• p38 Mitogen-Activated Protein Kinases
• DUSP1 protein, human
• Dual Specificity Phosphatase 1

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line
• Dual Specificity Phosphatase 1 (biosynthesis, genetics)
• Enzyme Activation
• Fatty Acids, Unsaturated (pharmacology)
• Humans
• Interleukin-6 (biosynthesis)
• Keratinocytes (metabolism, radiation effects)
• NF-kappa B (metabolism)
• RNA Interference
• RNA, Small Interfering
• Receptors, Leukotriene B4 (genetics)
• Signal Transduction (drug effects)
• Skin Diseases (drug therapy)
• Ultraviolet Rays
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)