Abstract
Stimulation of murine macrophages with LPS results in the coordinated activation of a set of proinflammatory cytokines and costimulatory molecules, including TNF-alpha, IL-6, IL-1, IL-8, IL-12, and CD80. Macrophage LPS-induced synthesis of IL-12 is inhibited following FcgammaR ligation; TNF-alpha 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-kappaB activation, but do not affect IL-1 or TNF-alpha signaling. Finally, macrophage FcgammaR ligation regulates MAST205 by inducing the rapid ubiquitination and proteasomal degradation of the protein.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis*
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Interleukin-12 Subunit p40
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Leukemia P388
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Ligands
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Macrophages, Peritoneal / enzymology
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C57BL
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / isolation & purification
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Microtubule-Associated Proteins / physiology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / isolation & purification
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Protein Serine-Threonine Kinases / physiology*
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / biosynthesis*
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RNA Interference / immunology
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Receptors, IgG / immunology
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Receptors, IgG / metabolism
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Receptors, IgG / physiology*
Substances
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Antigens, CD
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Fc gamma receptor IIA
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Interleukin-12 Subunit p40
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Ligands
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Lipopolysaccharides
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Microtubule-Associated Proteins
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Mtssk protein, mouse
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NF-kappa B
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Protein Subunits
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Receptors, IgG
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Interleukin-12
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Protein Serine-Threonine Kinases