Microtubule-Associated Serine/Threonine Kinase-205 kDa and Fcγ Receptor Control IL-12 p40 Synthesis and NF-κB Activation

Abstract

Stimulation of murine macrophages with LPS results in the coordinated activation of a set of proinflammatory cytokines and costimulatory molecules, including TNF-α, IL-6, IL-1, IL-8, IL-12, and CD80. Macrophage LPS-induced synthesis of IL-12 is inhibited following FcγR ligation; TNF-α 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-κB activation, but do not affect IL-1 or TNF-α signaling. Finally, macrophage FcγR ligation regulates MAST205 by inducing the rapid ubiquitination and proteasomal degradation of the protein.