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Janus Kinase-Signal Transducer and Activator of Transcription Mediates Phosphatidic Acid-Induced Interleukin (IL)-1 and IL-6 Production

Department of Biochemistry and Molecular Biology, and Aging-Associated Vascular Disease Research Center (C.H.L., H.-K.L., J.-R.K., S.-H.B.), Department of Preventive Medicine and Public Health (J.S.), College of Medicine, Yeungnam University, Daegu, Korea; and Division of Endocrinology, University of Pennsylvania, Philadelphia, Pennsylvania (Y.-S.L.)

We have found previously that phosphatidic acid (PA) can induce inflammatory mediators such as cytokines, which implies that PA plays a role in inflammatory response. In the present study, we provide evidence of the PA-mediated activation of the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which results in the production of interleukin (IL)-1 and IL-6. PA elicited the rapid phosphorylations of JAK2 and STAT1/3, and the subsequent nuclear translocation. Macrophages that had been transiently transfected with a luciferase reporter construct containing eight consecutive -interferon activating sequence (GAS) elements, a known STAT binding site, exhibited enhanced reporter gene activity in response to PA stimulation, which further supports the involvement of JAK-STAT activation in the PA-induced signaling pathway. Of the inflammatory cytokines, IL-1, IL-6, and tumor necrosis factor (TNF)- were detected in media from macrophages stimulated with PA. Moreover, the JAK2 inhibitor -cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490) abolished PA-induced IL-1 and IL-6 release but not TNF- production, which is consistent with the notion that IL-1 and IL-6 but not TNF- contain a STAT binding element in their promoter region. The knockdown of JAK2 in macrophages by small interfering RNA significantly attenuated PA-induced IL-1 and IL-6 production. In addition, JAK2 inhibitor suppressed PA-induced Akt phosphorylation, and the Akt inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocked GAS activation (GAS contains a promoter that responds to PA), suggesting that PA-mediated JAK2 activation leads to phosphatidylinositol 3-kinase/Akt phosphorylation and STAT activation, and the subsequent translocation of STAT to the nucleus. Together, our data demonstrate that PA-activated macrophages produce IL-1 and IL-6 and that these processes require the activation of the JAK2-STAT1/3 or JAK2-Akt-STAT signaling pathways.

Address correspondence to: Dr. Suk-Hwan Baek, Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung-5 Dong, Nam-Gu, Daegu 705-035, South Korea. E-mail: sbaek{at}med.yu.ac.kr