PT - JOURNAL ARTICLE AU - Barry L. Tepperman AU - Qing Chang AU - Brian D. Soper TI - Protein Kinase C Mediates Lipopolysaccharide- and Phorbol-Induced Nitric-Oxide Synthase Activity and Cellular Injury in the Rat Colon DP - 2000 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1249--1257 VI - 295 IP - 3 4099 - http://jpet.aspetjournals.org/content/295/3/1249.short 4100 - http://jpet.aspetjournals.org/content/295/3/1249.full SO - J Pharmacol Exp Ther2000 Dec 01; 295 AB - The role of protein kinase C (PKC) in lipopolysaccharide (LPS)- and phorbol ester-induced changes in rat colonic cellular integrity and Ca2+-independent inducible nitric-oxide synthase (iNOS) activity was investigated. LPS treatment (3 mg kg−1 i.p.) increased colonic cellular PKC activity within 1 h after administration. The percentage of nonviable cells and iNOS activity in response to LPS were reduced by pretreatment with the selective PKC antagonist GF 109203X (25 ng kg−1 i.v.). Pretreatment with the selective iNOS inhibitor 1400W (5 mg kg−1 s.c.) reduced the extent of cellular injury and iNOS activity but did not affect the increase in LPS-mediated PKC activation. Reduction of circulating neutrophils with anti-neutrophil serum reduced cell damage as well as the increases in PKC and iNOS activities in response to LPS. Intracolonic administration of the phorbol ester phorbol-12-myristate-13-acetate (PMA; 3 mg kg−1) increased colonic cellular PKC activity within 2 h after instillation. Cellular iNOS activity did not increase until 6 h after PMA administration. The colonic responses to PMA were eliminated by GF 109203X. The selective iNOS inhibitor 1400W reduced the increase in cell injury but did not affect the PKC activation in response to PMA. LPS treatment also increased in the proteins for PKC-α, PKC-δ, PKC-ε, and PKC-ζ. PMA treatment resulted in PKC-δ and PKC-ε translocation from cytosol to membrane. These data suggest that PKC mediates iNOS activation and subsequent colonic cell injury in response to LPS administration. The δ- and ε-isozymes appear to be most closely associated with these responses. The American Society for Pharmacology and Experimental Therapeutics