The Rac GTPase-controlled NADPH oxidase of human phagocytes is responsible for the formation of superoxide anion and other oxidants used by these cells for bacterial killing, and is also an important contributor to the inflammatory response. NADPH oxidase is directly stimulated by LPS in monocytes, and LPS serves to """"""""prime"""""""" oxidant production in other leukocytes, thereby enhancing the inflammatory damage occurring during septic shock. We will investigate the connections between Rac GTPase-regulated responses of leukocytes and the signaling mechanisms utilized by LPS. Novel lipid mediators formed in response to LPS will be tested for the ability to disrupt regulatory complexes of Rho family GTPases and RhoGDI. We will use both direct binding measurements and activity assays to evaluate possible effects on Rac signing by this mechanism. The contribution of Rac to the phagocyte oxidative responses induced by 125 will be tested using genetic approaches. Signaling via Rac to p38 MAPK will be examined as well, and we will evaluate the hypothesis that Rac- regulated kinases such as p38 control the coordinated assembly of the NADPH oxidase. Sites on NADPH oxidase components that are phosphorylated by p38 will be identified, and the contribution of this enzyme to oxidase assembly assessed. Finally, the possible connection of Rac GTPase to activation of the LPS- and cytokine-regulated transcription factor NF-kB will be evaluated. These studies should clarify the mechanisms by which LPS mediates inflammatory tissue damage during septic shock syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM037696-12
Application #
6271752
Study Section
Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Tanino, Yoshinori; Chang, Mary Y; Wang, Xintao et al. (2012) Syndecan-4 regulates early neutrophil migration and pulmonary inflammation in response to lipopolysaccharide. Am J Respir Cell Mol Biol 47:196-202
Manukyan, Maria; Nalbant, Perihan; Luxen, Sylvia et al. (2009) RhoA GTPase activation by TLR2 and TLR3 ligands: connecting via Src to NF-kappa B. J Immunol 182:3522-9
Kurahashi, Kiyoyasu; Sawa, Teiji; Ota, Maria et al. (2009) Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 296:L198-209
Lu, Miao; Lin, Su-Chang; Huang, Yihua et al. (2007) XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell 26:689-702
Lombardo, Eleuterio; Alvarez-Barrientos, Alberto; Maroto, Beatriz et al. (2007) TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-alpha autocrine signalling. J Immunol 178:3731-9
da Silva Correia, J; Miranda, Y; Leonard, N et al. (2007) Regulation of Nod1-mediated signaling pathways. Cell Death Differ 14:830-9
Kang, Young Jun; Kim, Sung Ouk; Shimada, Shigeki et al. (2007) Cell surface 4-1BBL mediates sequential signaling pathways 'downstream'of TLR and is required for sustained TNF production in macrophages. Nat Immunol 8:601-9
Xu, Yue; Huang, Shuang; Liu, Zheng-Gang et al. (2006) Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 281:8788-95
Tan, Roderick J; Lee, Janet S; Manni, Michelle L et al. (2006) Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury. Am J Respir Cell Mol Biol 34:226-32
Zhou, Huamin; Zheng, Min; Chen, Jianming et al. (2006) Determinants that control the specific interactions between TAB1 and p38alpha. Mol Cell Biol 26:3824-34

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