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An Atypical Protein Kinase C (PKC) Plays a Critical Role in Lipopolysaccharide-Activated NF-B in Human Peripheral Blood Monocytes and Macrophages¹

XueSong Huang^*, Ling-Yu Chen, Astrid M. Doerner^*, Warren W. Pan, Laura Smith^*, Shuang Huang, Thomas J. Papadimos^* and Zhixing K. Pan^2,*,

^* Department of Medical Microbiology & Immunology, Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614; and Department of Immunology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

We have reported that the bacterial LPS induces the activation of NF-B and inflammatory cytokine gene expression and that this requires the activity of small GTPase, RhoA. In this study, we show that an atypical protein kinase C isozyme, PKC, associates functionally with RhoA and that PKC acts as a signaling component downstream of RhoA. Stimulation of monocytes and macrophages with LPS resulted in PKC activation and that inhibition of PKC activity blocks both LPS-stimulated activation of NF-B and IL-1β gene expression. Our results also indicate that transforming growth factor β-activated kinase 1 acts as a signaling component downstream of PKC in cytokine gene transcription stimulated by LPS in human peripheral blood monocytes and macrophages. The specificity of this response suggests an important role for the Rho GTPase/PKC/transforming growth factor β-activated kinase 1/NF-B pathway in host defense and in proinflammatory cytokine synthesis induced by bacterial LPS.

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¹ This work was supported by United States Public Health Service Grant AI43524 (to Z.K.P.) and National Institutes of Health Training Grant T32 AI 07469 (to L.-Y.C.). This work was also supported in part by the Sam and Ross Stein Charitable Trust and National Institutes of Health Grant M01RR00833 provided to the General Clinical Research Center of the Scripps Research Institute.

² Address correspondence and reprint requests to Dr. Zhixing K. Pan, Department of Medical Microbiology and Immunology, University of Toledo Medical Center, 3035 Arlington Avenue, Toledo, OH 43614. E-mail address: kevin.pan{at}utoledo.edu

³ Abbreviations used in this paper: PKC, protein kinase C; aPKC, atypical PKC; EMSA, electrophoretic mobility shift assay; PS, PKC pseudosubstrate inhibitor; PAK1, p21-activating kinase 1; TAK1, transforming growth factor β-activated kinase 1; siRNA, small inhibitory RNA.