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Published online before print January 23, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0603280

Received for publication June 18, 2003.
Revised December 2, 2003.
Accepted for publication December 12, 2003.

Article

Activation of phosphatidylinositol 3-kinase and c-Jun-N-terminal kinase cascades enhances NF-B-dependent gene transcription in BCG-stimulated macrophages through promotion of p65/p300 binding

Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense, Campos, Rio de Janeiro, Brazil

^@ To whom correspondence should be addressed. E-mail: elena{at}uenf.br.

	Abstract

The proinflammatory response of infected macrophages is an important early host defense mechanism against mycobacterial infection. Mycobacteria have been demonstrated to induce proinflammatory gene transcription through the Toll-like receptors (TLR)2 and TLR 4, which initiate signaling cascades leading to nuclear factor (NF)-B activation. The main transduction pathway responsible for NF-B activation has been established and involves the MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor-6, NF-inducing kinase, and inhibitor of B kinase complex. The role of other kinase cascades triggered by mycobacteria in the NF-B activation is less clear. We herein examine the role of the mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI-3K) cascades in the expression of the bacillus Calmette-Guerin (BCG) mycobacteria-induced NF-B-dependent genes, macrophage-inflammatory protein-2 (MIP-2) and inducible nitric oxide (NO) synthase. Specific pharmacological inhibition of the PI-3K, c-jun-N-terminal kinase (JNK), and to a smaller extent, p38 MAPK but not extracellular-regulated kinase, suppressed NF-B-dependent reporter gene transcription and MIP-2 and NO secretion in BCG-induced RAW264.7 macrophages. A similar effect was obtained following molecular inhibition of JNK via JNK-interacting protein-1 overexpression. In addition, a kinase-dead mutant of MAPK kinase kinase-1, the up-stream regulator of JNK, also proved to be a potent inhibitor of NF-B-reporter activity. The effect of inhibitors was mediated by the down-regulation of NF-B transcription activity and without effecting its nuclear translocation. These data suggest an indirect mechanism of the NF-B regulation by these kinases, probably through p65 phosphorylation and improved binding to the p300 transcription coactivator. The data obtained demonstrate that PI-3K, JNK, and p38 MAPK activation by mycobacteria enhance NF-B-driven gene expression contributing to the proinflammatory macrophage response.

Key Words: RAW264.7 cells • MIP-2 • iNOS • signal transduction

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