ABSTRACT
NKT cells are known to rapidly produce a large amount of cytokines upon activation. Although a number of signaling pathways that regulate the development of NKT cells have been identified, the signaling pathways involved in the regulation of NKT cell cytokine production remain unclear. In this study, we show that the p38 MAPK pathway is dispensable for the development of NKT cells. However, NKT cell cytokine production and NKT-mediated liver damage are highly dependent on activation of this pathway. p38 MAPK does not substantially affect cytokine gene expression in NKT cells, but it regulates the synthesis of cytokines through the Mnk-eIF4E pathway. Thus, in addition to gene expression, translational regulation by p38 MAPK could be a novel mechanism that contributes to the overall production of cytokine by NKT cells.
Subject(s)
Cytokines/biosynthesis , Cytokines/genetics , MAP Kinase Signaling System/immunology , Natural Killer T-Cells/immunology , Natural Killer T-Cells/metabolism , Protein Modification, Translational/immunology , Animals , Cell Differentiation/genetics , Cell Differentiation/immunology , Cells, Cultured , Enzyme Activation/genetics , Enzyme Activation/immunology , Liver Diseases/enzymology , Liver Diseases/genetics , Liver Diseases/immunology , MAP Kinase Kinase 3/deficiency , MAP Kinase Kinase 3/genetics , MAP Kinase Kinase 3/physiology , MAP Kinase Kinase 6/deficiency , MAP Kinase Kinase 6/genetics , MAP Kinase Kinase 6/physiology , MAP Kinase Signaling System/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Natural Killer T-Cells/enzymologyABSTRACT
Natural killer T (NKT) cells comprise a novel T-lymphocyte subset that can influence a wide variety of immune responses through their ability to secrete large amounts of a variety of cytokines. Although variation in NKT-cell number and function has been extensively studied in autoimmune disease-prone mice, in which it has been linked to disease susceptibility, relatively little is known of the natural variation of NKT-cell number and function among normal inbred mouse strains. Here, we demonstrate strain-dependent variation in the susceptibility of C57BL/6J and BALB/cJ mice to NKT-mediated airway hyperreactivity, which correlated with significant increases in serum interleukin-4 (IL-4) and IL-13 elicited by the synthetic glycosphingolipid alpha-galactosylceramide. Examination of NKT-cell function revealed a significantly greater frequency of cytokine-producing NKT cells in C57BL/6J versus BALB/cJ mice as well as significant differences in the kinetics of NKT-cell cytokine production. Extension of this analysis to a panel of inbred mouse strains indicated that variability in NKT-cell cytokine production was widespread. Similarly, an examination of NKT-cell frequency revealed a significantly greater number of liver NKT cells in the C57BL/6J mice versus BALB/cJ mouse livers. Again, examination of a panel of inbred mouse strains revealed that liver NKT-cell numbers were quite variable, spanning over a 100-fold range. Taken together, these results demonstrate the presence of widespread natural variation in NKT-cell number and function among common inbred mouse strains, which may have implications for the examination of the influence of NKT cells in immune responses and disease pathogenesis among different genetic backgrounds.
