We have previously shown that jacalin, a CD4+ T cell lectin, induces phosphorylation of intracellular events, moderate levels of interleukin (IL)-2 secretion. We have also shown that in the presence of CD28 costimulation, jacalin induces IL-4 secretion. In the present study, we showed that stimulation of normal CD4+ T cells with jacalin plus CD28 cross-linking (CD28XL) resulted in phosphorylation of signal transducer and activator of transcription (STAT)-6 and expression of Bcl-2 and Bcl-xL, which were inhibited significantly when cells were cultured in the presence of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. We further generated jacalin-induced CD4+ T cell blasts, examined the effects of CD28XL, and observed enhanced up-regulation of p38 and activation of STAT-6, Bcl-2, and Bcl-xL. Engagement of CD28 alone induced a marked degree of phosphorylation of p38 MAPK and IL-4 secretion in memory T cells (jacalin blasts), whereas in naïve T cells, jacalin plus CD28XL was required to induce these molecules. Incubation of cells with p38 inhibitor prior to CD28XL resulted in down-modulation of all these molecules. Further treatment with IL-4 has not reversed this trend. Our studies imply that p38 MAPK may play an important role in induction of these molecules and a putative role in protecting cells from undergoing apoptosis.
Cytokine interactions in health & disease are very complex. There are conflicting reports on the cytokine IL-18 and its role in Th1 versus Th2 shift. The hypothesis that STAT-6 is expressed in monocyte/macrophages and that cytokine IL-18 has an effect on the phosphorylation of STAT-6 is addressed. Monocyte/macrophages were isolated by negative selection. The data indicates that the optimum concentration of IL-18 required for stimulation is 10μg/1x106 cells and 72 hour culture period is the optimum time for the induction of maximum levels of STAT-6 phosphorylation. We also observed total tyrosine phosphorylation of several intracellular proteins. Based on these studies, we propose that macrophages respond to IL-18 via STAT-6 phosphorylation and that IL-18 induces mitotic activity in monocyte/macrophages. Our data suggest that IL-18 actsin a more subtle manner as a costimulatory factor in the activation of STAT-6 in monocytes and provides evidence for a new immunoregulatoryeffect of the proinflammatory cytokine IL-18 on monocytes. Grant from C.W.Post Campus Research Committee of Long Island University, New York supported this work.
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