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J. Biol. Chem., Vol. 279, Issue 16, 15954-15960, April 16, 2004

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Role of Protein Kinase C Isoforms in the Regulation of Interleukin-13-induced 15-Lipoxygenase Gene Expression in Human Monocytes^*

Bo Xu, Ashish Bhattacharjee, Biswajit Roy, Gerald M. Feldman¶, and Martha K. Cathcart||

From the Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the ^¶Division of Monoclonal Antibodies, Office of Therapeutics, Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

We reported previously that interleukin-13 (IL-13) induces tyrosine phosphorylation/activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6 in primary human monocytes. We recently revealed that p38 MAPK-mediated serine phosphorylation of both Stat1 and Stat3 is required for the induction of 15-lipoxygenase (15-LO) expression by IL-13. In this study, we present data indicating that another serine/threonine kinase, PKC, is also required for IL-13-induced 15-LO expression. PKC, a member of the novel protein kinase C (PKC) subclass, was rapidly phosphorylated and activated upon exposure to IL-13. Treatment of cells with rottlerin, a PKC inhibitor, blocked IL-13-induced 15-LO mRNA and protein expression, whereas Go6976, an inhibitor of the conventional PKC subclass, had no inhibitory effects. Down-regulation of cellular PKC protein levels by PKC-specific antisense oligodeoxyribonucleotides also inhibited 15-LO expression markedly. IL-13-induced 15-LO expression resulted in significant inhibition of synthesis of the potent chemotactic factor leukotriene B₄, and that process was reversed by rottlerin, presumably through the blockage of PKC-dependent 15-LO expression. Furthermore, our data demonstrate that IL-13-mediated activation of PKC and p38 MAPK are independent pathways, because inhibition of one kinase activity had no effect on the other, suggesting that the two pathways act in parallel to regulate the downstream targets necessary for 15-LO expression. Inhibition of PKC activation by rottlerin also markedly attenuated IL-13-induced Stat3 DNA binding activity. Our findings indicate that PKC plays an important role in regulating IL-13-induced 15-LO expression in human monocytes and subsequently modulates the inflammatory responses mediated by 15-LO products.

Received for publication, January 14, 2004

^* These studies were supported by National Institutes of Health Grant HL51068 (to M. K. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this manuscript and are considered joint first authors.

^|| To whom correspondence should be addressed: Dept. of Cell Biology, Lerner Research Inst., Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-5222; Fax: 216-444-9404; E-mail: cathcam{at}ccf.org.

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