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Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C and Tyrosine-Phosphorylated Stat3¹

Ashish Bhattacharjee^*, Bo Xu^*, David A. Frank, Gerald M. Feldman and Martha K. Cathcart^2,*

^* Department of Cell Biology, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Monoclonal Antibodies, Office of Therapeutics, Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892

Our previous studies demonstrated that the IL-13-induced 15-lipoxygenase expression in primary human monocytes is regulated by the activation of both Stat1 and Stat3 and by protein kinase C (PKC). IL-13 stimulated the phosphorylation of Stat3 on both Tyr⁷⁰⁵ and Ser⁷²⁷. In this study we show that IL-13 induces the association of PKC with Stat3, not with Stat1, and is required for Stat3 Ser⁷²⁷ phosphorylation. We found a novel IL-13-dependent cytosolic signaling complex of PKC and tyrosine-phosphorylated Stat3. A tyrosine kinase inhibitor blocked PKC association with Stat3 as well as Stat3 Ser⁷²⁷ phosphorylation. We therefore hypothesized that tyrosine phosphorylation was required for Stat3 interaction with PKC and subsequent PKC-dependent phosphorylation of Stat3 Ser⁷²⁷. We developed an efficient transfection protocol for human monocytes. Expression of Stat3 containing a mutation in Tyr⁷⁰⁵ inhibited the association of PKC with Stat3 and blocked Stat3 Ser⁷²⁷ phosphorylation, whereas transfection with wild-type Stat3 did not. Furthermore, by transfecting monocytes with Stat3 containing mutations in Tyr⁷⁰⁵ or Ser⁷²⁷ or with wild-type Stat3, we demonstrated that both Stat3 tyrosine and serine phosphorylations are required for optimal binding of Stat3 with DNA and maximal expression of 15-lipoxygenase, an important regulator of inflammation and apoptosis.

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.

¹ This work is supported by Grant HL51068 from the National Institutes of Health (to M.K.C.) and by the General Clinical Research Center Grant M01 RR-018390.

² Address correspondence and reprint requests to Dr. Martha K. Cathcart, Department of Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: cathcam{at}ccf.org

³ Abbreviations used in this paper: 15-LO, 15-lipoxygenase; PBM, peripheral blood monocyte; ODN, oligodeoxyribonucleotide; PKC, protein kinase C; WT, wild type.

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