): 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043524-06
Application #
6706979
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Dong, Gang
Project Start
2000-04-01
Project End
2005-05-31
Budget Start
2004-04-01
Budget End
2005-05-31
Support Year
6
Fiscal Year
2004
Total Cost
$183,750
Indirect Cost
Name
University of Toledo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Pan, Yiqing; Xu, Chen; Pan, Zhixing K (2017) MKP-1 negative regulates Staphylococcus aureus induced inflammatory responses in Raw264.7 cells: roles of PKA-MKP-1 pathway and enhanced by rolipram. Sci Rep 7:12366
Pan, Zhixing K; Fisher, Chris; Li, Jian-Dong et al. (2011) Bacterial LPS up-regulated TLR3 expression is critical for antiviral response in human monocytes: evidence for negative regulation by CYLD. Int Immunol 23:357-64
Pan, Warren W; Li, Jain-Dong; Huang, Shuang et al. (2010) Synergistic activation of NF-{kappa}B by bacterial chemoattractant and TNF{alpha} is mediated by p38 MAPK-dependent RelA acetylation. J Biol Chem 285:34348-54
Chen, Ling-Yu; Pan, Warren W; Chen, Miao et al. (2009) Synergistic induction of inflammation by bacterial products lipopolysaccharide and fMLP: an important microbial pathogenic mechanism. J Immunol 182:2518-24
Su, S; Li, Y; Luo, Y et al. (2009) Proteinase-activated receptor 2 expression in breast cancer and its role in breast cancer cell migration. Oncogene 28:3047-57
Bohman, Keith D; Papadimos, Thomas J; Gottwald, Lorie D et al. (2009) Perniosis (chilblains) masquerading as CA-MRSA: a case report. Cases J 2:6500
Huang, XueSong; Chen, Ling-Yu; Doerner, Astrid M et al. (2009) An atypical protein kinase C (PKC zeta) plays a critical role in lipopolysaccharide-activated NF-kappa B in human peripheral blood monocytes and macrophages. J Immunol 182:5810-5
Chen, Haoming; Zhu, Genfeng; Li, Yong et al. (2009) Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res 69:9228-35
Mukherjee, Sumanta; Chen, Ling-Yu; Papadimos, Thomas J et al. (2009) Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. J Biol Chem 284:29391-8
Chen, Ling-Yu; Pan, Zhixing K (2009) Synergistic activation of leukocytes by bacterial chemoattractants: potential drug targets. Endocr Metab Immune Disord Drug Targets 9:361-70

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