LPS and phorbol esters induce nitric oxide release in rat hepatocytes via protein kinase C activation, but exhibit an antagonistic effect when combined.
Combined LPS-phorbol ester exposure antagonizes hepatocyte nitric oxide release; hypothesis-generating for PKC modulation in hepatic inflammation, requiring in vivo validation.
The incubation of primary cultures of rat hepatocytes with lipopolysaccharide (LPS) or biologically active phorbol esters promotes the release of nitric oxide to the incubation medium. This process is the result of the induction of the Ca 2+ - and calmodulinindependent form of nitric oxide synthase. Both the release of nitric oxide to the incubation medium and the expression of nitric oxide synthase activity exhibited a lag period of about 45-60 min after cell stimulation. Exposure of hepatocytes to both stimuli produced an antagonistic effect on nitric oxide release, with a half-maximal inhibition obtained with 14 nM phorbol 12,13-dibutyrate at saturating concentration of LPS. Incubation of cells with α-phorbol 12,13- didecanoate failed to counteract the effect of LPS or to induce nitric oxide synthase, suggesting that activation of protein kinase C was involved in this process.
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John Wiley (1993) studied this question.
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