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i Proteins
1 Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC, USA
2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
3 Experimental Pathology and Microbiology, Medical University of Messina, Messina, OH, Italy
4 Pharmacology, Medical University of South Carolina, Charleston, SC, USA
* To whom correspondence should be addressed. E-mail: cookja{at}musc.edu.
Heterotrimeric Gi proteins may play a role in lipopolysaccharide (LPS) activated signaling through Toll-like receptor 4 (TLR4) leading to inflammatory mediator production. Although LPS is a TLR4 ligand, the gram-positive bacteria Staphylococcus aureus (SA) is a TLR2 ligand, and Group B Streptococci (GBS) is neither a TLR2 nor TLR4 ligand but is MyD88 dependent. We hypothesized that genetic deletion of Gi proteins would alter mediator production induced by LPS and gram-positive bacterial stimulation. We examined genetic deletion of G
i2 or Gi1/3 protein in Gi2(-/-) or Gi1/3(-/-) knockout mice. LPS- and heat killed SA- or GBS- induced mediator production in splenocytes or peritoneal macrophages (M[[Oslash]];) was investigated. There were significant increases in LPS-, SA- and GBS-induced production of TNF, and IFN
in splenocytes from Gi2(-/-) mice compared with wild type (WT) mice. Also LPS induced TNF was increased in splenocytes from Gi1/3(-/-) mice. In contrast to splenocytes, LPS-, SA- and GBS-induced TNF, IL-10, and TxB2 productionin were decreased in M[[Oslash]]; harvested from Gi2(-/-) mice. Also LPS- induced production of IL-10 and TxB2 was decreased in M[[Oslash]]; from Gi1/3(-/-) mice. In subsequent in vivo studies, TNF levels following LPS challenge were significantly greater in Gi2(-/-) mice than WT mice. Also myeloperoxidase activity, a marker of tissue neutrophil infiltration, was significantly increased in the gut and lung from LPS treated Gi2(-/-) mice compared to WT mice. These data suggest that Gi proteins differentially regulate murine TLR mediated inflammatory cytokine production in a cell specific manner in response to both LPS and gram-positive microbial stimuli.
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