Exp Mol Med.  2012 Jun;44(6):378-386.

12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity

• Lee JW
• Ryu HC
• Ng YC
• Kim C
• Wei JD
• Sabaratnam V
• Kim JH

Abstract

12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) is an enzymatic product of prostaglandin H2 (PGH2) 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-kappaB). 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-kappaB, 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-kappaB, 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.

Keyword

dermatitis; dual specificity phosphatase 1; 12-hydroxy-5,8,10-heptadecatrienoic acid; interleukin-6; ultraviolet rays

MeSH Terms

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