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Differential Role of Janus Family Kinases (JAKs) in Interferon-–Induced Lung Epithelial ICAM-1 Expression: Involving Protein Interactions between JAKs, Phospholipase C, c-Src, and STAT1

Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan (Y.-J.C., C.-C.C.); and the Department of Medicine and Cell Biology, Washington University, School of Medicine, St. Louis, Missouri (M.J.H.)

The signaling pathway for IFN-–mediated induction of ICAM-1 expression was further studied in human NCI-H292 epithelial cells. The Tyr701 phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by interferon- (IFN-) and 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by the protein kinase C (PKC) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the Src kinase inhibitor PP2. An association between c-Src and STAT1 was increased by IFN- and TPA, indicating the direct phosphorylation of STAT1 by PKC-dependent c-Src activation. Tyrosine phosphorylation of Janus kinases (JAK) 1/2 was induced by IFN- but not by TPA. In addition, ICAM-1 promoter activity induced by IFN-, but not that induced by TPA, was inhibited by the dominant-negative JAK1 and JAK2 mutants. IFN-–induced tyrosine phosphorylation of phospholipase C (PLC)- was inhibited by AG 490 (a JAK inhibitor), and the association between JAK1/2 and PLC- was increased after IFN- treatment, indicating the activation of PLC- via JAK1/2 phosphorylation. ICAM-1 promoter activities induced by the overexpression of wild-type JAK1- and PLC-2 were blocked by the PLC2 mutant or the dominant-negative PKC (LysArg), c-Src (LysMet), or STAT1 (Y701M) mutants, but not by dominant-negative STAT3 (DN) mutants. These results confirmed that IFN- activated PLC- via JAK1/2 phosphorylation to induce PKC, c-Src, STAT1 activation, and ICAM-1 expression. The association between JAK1/2 and STAT1 was increased by IFN- but not by TPA. It was inhibited by AG 490 but not by U73122, indicating the possible involvement of the JAK1/2-STAT1 pathway. All the results show that IFN- induces ICAM-1 expression by two different pathways in NCI-H292 epithelial cells. One is the JAK1/2-dependent PLC- pathway inducing the activations of PKC, c-Src, and STAT1, and the other is the direct activation of STAT1 by JAK1/2.

Received May 30, 2003; accepted November 13, 2003.

Address correspondence to: Dr. Ching-Chow Chen, Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road, 1st Section, Taipei 10018, Taiwan. E-mail: ccchen{at}ha.mc.ntu.edu.tw.

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