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Microtubule-Associated Serine/Threonine Kinase-205 kDa and Fc Receptor Control IL-12 p40 Synthesis and NF-B Activation^1,2

Hui Zhou^3,4,*, Huabao Xiong^4,*, Hongxing Li^*, Scott E. Plevy, Paul D. Walden, Massimo Sassaroli, Glenn D. Prestwich^¶ and Jay C. Unkeless^5,*

^* Immunobiology Center and Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029; Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Urology, New York University School of Medicine, New York, NY 10016; and ^¶ Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112

Stimulation of murine macrophages with LPS results in the coordinated activation of a set of proinflammatory cytokines and costimulatory molecules, including TNF-, IL-6, IL-1, IL-8, IL-12, and CD80. Macrophage LPS-induced synthesis of IL-12 is inhibited following FcR ligation; TNF- secretion is unchanged. We report that microtubule-associated serine/threonine kinase-205 kDa (MAST205) is required for LPS-induced IL-12 synthesis. RNA interference-mediated suppression of MAST205 results in the inhibition of LPS-stimulated IL-12 promoter activity and IL-12 secretion, from both J774 cells and bone marrow-derived macrophages. Similarly, dominant-negative MAST205 mutants inhibit LPS-stimulated IL-12 synthesis and NF-B activation, but do not affect IL-1 or TNF- signaling. Finally, macrophage FcR ligation regulates MAST205 by inducing the rapid ubiquitination and proteasomal degradation of the protein.

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