Gadd45alpha regulates p38-dependent dendritic cell cytokine production and Th1 differentiation.
Gadd45alpha inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr(323). Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45alpha(-/-) mice. Despite constitutively increased p38 activity in Gadd45alpha(-/-) T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45alpha(-/-) DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45alpha(-/-) recipients had a diminished Th1 response to STAg, whereas Gadd45alpha(-/-) T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45alpha has tissue-specific and opposing functions on p38 activity, and Gadd45alpha-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.
Jirmanova
Ludmila
L
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jankovic
Dragana
D
Fornace
Albert J
AJ
Ashwell
Jonathan D
JD
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D016764:Cell Polarity; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097642:GADD45 Proteins
D000953:Antigens, Protozoan; D019013:CD40 Antigens; D018797:Cell Cycle Proteins; D016207:Cytokines; D018664:Interleukin-12; D009687:Nuclear Proteins; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C094052:soluble tachyzoite antigen, Toxoplasma gondii