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Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages

, : Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. European Journal of Immunology 33(3): 597-605

Recent evidence suggests a role for phosphatidylinositol (PI) 3-kinase in various inflammatory responses. In this study, the consequences of LPS-induced PI 3-kinase activation on cytokine and chemokine expression and the intracellular mechanisms of inflammatory activation were examined in mouse macrophages. LPS stimulation induced a complex formation between PI 3-kinase and myeloid differentiation factor 88 (MyD88), which was followed by an induction of IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein (MIP)-2. The induction of IL-1beta, but not of MIP-2 or TNF-alpha, was blocked by the PI 3-kinase inhibitors LY294002 and wortmannin. The nuclear factor-kappaB (NF-kappaB) inhibitor pyrrolidinedithiocarbamate (PDTC) blocked the induction of IL-1beta and TNF-alpha, but had no effect on MIP-2 expression. Inhibition of PI 3-kinase decreased the LPS-induced transcriptional activity of NF-kappaB, but it had no effect on the nuclear DNA binding activity of NF-kappaB. These findings suggest that, while NF-kappaB nuclear localization and DNA binding are necessary, they are not sufficient for transcriptional activation of the IL-1beta gene in the absence of PI 3-kinase activity. Taken together, our results demonstrate that activation of Toll-like receptor (TLR)-4 results in PI 3-kinase-MyD88 complex formation, and that PI 3-kinase activity selectively leads to cytokine induction downstream of TLR4.


PMID: 12616480

DOI: 10.1002/eji.200323376

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