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Molecular and Cellular Biology, June 2003, p. 3918-3928, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3918-3928.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3

Bo Xu,1 Ashish Bhattacharjee,1 Biswajit Roy,1 Hong-Min Xu,1 David Anthony,1 David A. Frank,2 Gerald M. Feldman,3 and Martha K. Cathcart1*

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195,1 Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,2 Division of Monoclonal Antibodies, Office of Therapeutics, Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208923

Received 2 October 2002/ Returned for modification 19 November 2002/ Accepted 12 March 2003

Interleukin-13 (IL-13) is a cytokine secreted by Th2 lymphocytes that is capable of inducing expression of 15-lipoxygenase (15-LO) in primary human monocytes. We recently demonstrated that induction of 15-LO requires the activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6. Since IL-13-induced 15-LO expression was inhibited by H7 (a serine-threonine kinase inhibitor), we predicted that Stat serine phosphorylation may also be crucial for 15-LO expression. In this study, we present evidence indicating that IL-13-induced 15-LO mRNA expression was detectable as early as 1 h by real-time reverse transcription-PCR. We found that IL-13 induced a time-dependent serine phosphorylation of both Stat1 and Stat3, detectable at 15 min after IL-13 treatment. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) was detected in a time-dependent fashion, with peak phosphorylation at 15 min after IL-13 treatment. SB202190, a p38 MAPK-specific inhibitor, markedly inhibited IL-13-induced Stat1 and Stat3 serine phosphorylation as well as DNA binding. Furthermore, treatment of cells with Stat1 or Stat3 decoys significantly impaired IL-13-induced 15-LO expression. Taken together, our results provide the first evidence that IL-13 induces p38 MAPK phosphorylation/activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. Both of these events are important steps in IL-13-induced 15-LO expression in human monocytes.

* Corresponding author. Mailing address: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216) 444-5222. Fax: (216) 444-9404. E-mail: cathcam{at}ccf.org.

Molecular and Cellular Biology, June 2003, p. 3918-3928, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3918-3928.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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