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Title: Calcium-dependent p38 phosphorylation is important for memory CD4 T cell effector cytokine transcription and mRNA stabilization.

Author
item GUO, LILING - NIH BETHESDA, MD
item URBAN JR, JOSEPH - 1235-25-00
item JANKOVIC, DRAGANA - NIH BETHESDA, MD
item ZHU, ZINFANG - NIH BETHESDA, MD
item PAUL, WILLIAM - NIH BETHESDA, MD

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2008
Publication Date: 9/15/2008
Citation: Guo, L., Urban Jr, J., Jankovic, D., Zhu, Z., Paul, W. 2008. Calcium-dependent p38 phosphorylation is important for memory CD4 T cell effector cytokine transcription and mRNA stabilization. Journal of Immunology. 18(6):3984-3993.

Interpretive Summary: A characteristic of the acquired immune system that responds to infection is rapid induction of effector molecules and cells to neutralize the spread of the pathogen. This normally involves the engagement of antigens released by the pathogen and other secondary signals that activate cells specifically. The current study describes the activation of cells in mice infected with both worm and protozoan parasites and how these cells are stimulated by activation molecules that mimic the rapid influx of calcium to cause cell differentiation and the release of effector cytokine proteins. The results show that cells primed in the animal to respond to infection can be rapidly induced by ionomycin to activate intracellular signaling molecules that turn on cytokines that act to control the infection. These results indicate that both early activation and longevity of the message for these cytokines enhances the effectiveness of the response. It also suggests that there are unknown molecules produced by the pathogen that serve to replace the function of ionomycin in the animal. This information provides a useful target to test for products secreted or produced by parasites to more efficacy activate the immune response to control disease. It is of interest to scientists that study immune function and can provide insights into better vaccine composition to improve animal health.

Technical Abstract: PMA and ionomycin are often used for in vitro T cell stimulation, as a mimic of TCR-mediated activation. Here we report that ionomycin alone induces substantial production of IL-4 and IFN-gamma, but not IL-2, from in vivo and in vitro generated Th2 and Th1 cells, respectively. Ionomycin induces p38 phosphorylation through a calcium-dependent pathway. Blocking p38 activity by the use of p38 inhibitors markedly inhibits ionomycin-induced IL-4 and IFN-gamma production and RNAi-mediated “knocking down” of p38 inhibits IL-4 induction. p38 regulates IL-4 production both through promoting transcription and by mRNA stabilization. p38 is also phosphorylated during TCR-mediated signaling through a calcium dependent pathway and p38 is required for optimal IL-4 and IFN-gamma production in response to peptide/antigen-presenting cells (APC) stimulation of cognate T cells or anti-CD3/CD28 T cell activation. The production of effector cytokines in response to ionomycin alone suggests mechanisms to amplify responses of effector and of memory T cells.