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Implication of G i proteins and Src tyrosine kinases in endotoxin-induced signal transduction events and mediator production

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, Medical University of Messina, Messina, Italy

Olga G. Romanenko

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA

Kelly Guyton

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA

Sarah Ashton

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA

Francesco Squadrito

Institute of Pharmacology, Medical University of Messina, Messina, Italy

Perry V. Halushka

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

James A. Cook

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA

Previous studies have suggested that heterotrimeric G proteins and tyrosine kinases may be involved in lipopolysaccharide (LPS) signaling events. Signal transduction pathways activated by LPS were examined in human promonocytic THP-1 cells. We hypothesized that G_i proteins and Src tyrosine kinase differentially affect mitogen-activated protein (MAP) kinases (MAPK) and nuclear factor kappa (NF- B) activation. Post-receptor coupling to G _i proteins were examined using pertussis toxin (PTx), which inhibits G _i receptor-coupling. The involvement of the Src family of tyrosine kinases was examined using the selective Src tyrosine kinase inhibitor pyrazolopyrimidine-2 (PP2). Pretreatment of THP-1 cells with PTx attenuated LPS-induced activation of c-Jun-N-terminal kinase (JNK) and p38 kinase, and production of tumor necrosis factor-alpha (TNF-) and thromboxane B₂ (TxB₂). Pretreatment with PP2 inhibited TNF- and TxB₂ production, but had no effect on p38 kinase or JNK signaling. Therefore, the G _i-coupled signaling pathways and Src tyrosine kinase-coupled signaling pathways are necessary for LPS-induced TNF- and TxB₂ production, but differ in their effects on MAPK activation. Neither PTx nor PP2 inhibited LPS-induced activation of interleukin receptor activated kinase (IRAK) or inhibitedtranslocation of NF- B. However, PP2 inhibitedLPS-inducedNF-B transactivation of a luciferase reporter gene construct in a concentration-dependent manner. Thus, LPS induction of Src tyrosine kinases may be essential in downstream NF- B transactivation of genes following DNA binding. PTx had no effect on NF- B activation of the reporter construct. These data suggest upstream divergence in signaling through G _i pathways leading to MAPK activation and other signaling events leading to I B degradation and NF- B DNA binding.

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