): Proinflammatory cytokines, such as IL-1, TNF and IL-6 are produced by leukocytes in response to bacteria or bacterial components. Although beneficial to host defense at the time of infection, leukocyte activation, when inappropriate or exaggerated, can contribute to numerous pathological conditions. The inflammatory response to bacteria or bacterial components produced by infecting bacteria involves leukocyte transcription activation and specific gene expression. Although a great deal has been learned during the past few years about the synthesis and release of proinflammatory cytokines by leukocytes, relatively little is known about the intracellular events that lead to leukocyte gene transcription. This application will address this gap by investigating the fMLP-stimulated intracellular signaling events that lead to the transcription and synthesis of proinflammatory cytokines in leukocytes. In preliminary experiments, the P.I. has shown that fMLP or LPS activate NF-kB and thereby induce proinflammatory cytokine IL-1b gene expression in human peripheral blood monocytes. Furthermore that RhoA, a member of the Rho family of GTPases, is a critical signaling molecule triggered by both fMLP and LPS stimuli that cause leukocyte cytokine gene expression. The focus, therefore, of this proposal will be to: 1) Characterize the role of the Rho family of low molecular weight G proteins in fMLP-induced IL-1b gene transcription in monocytes; 2) Analyze the mechanisms of Rho activation stimulated by fMLP; 3) Identify the targets of Rho GTPase which lead to leukocyte cytokine gene transcription. The information obtained from this project is expected to extend our knowledge of the signal transduction pathways leading to proinflammatory cytokine gene transcription occurring in response to invading bacteria. This information may lead to a fuller understanding of the role of bacterial infections in the pathogenesis of inflammatory disorders.
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