Microtubule-associated serine/threonine kinase-205 kDa and Fc gamma receptor control IL-12 p40 synthesis and NF-kappa B activation.
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.
Zhou
Hui
H
Immunobiology Center and Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Xiong
Huabao
H
Li
Hongxing
H
Plevy
Scott E
SE
Walden
Paul D
PD
Sassaroli
Massimo
M
Prestwich
Glenn D
GD
Unkeless
Jay C
JC
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40; D007941:Leukemia P388; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D034622:RNA Interference / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D053762:Interleukin-12 Subunit p40; D008024:Ligands; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; C084505:Mtssk protein, mouse; D016328:NF-kappa B; D021122:Protein Subunits; D017452:Receptors, IgG; D018664:Interleukin-12; D017346:Protein Serine-Threonine Kinases