Cyclic GMP and guanylate cyclase mediate lipopolysaccharide‐induced Kupffer cell tumor necrosis factor‐ α synthesis

Tumor necrosis factor‐ α (TNF‐ α ) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF‐ α in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon‐ γ on TNF‐ α production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF‐ α synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS‐induced KC TNF‐ α synthesis. Exogenous 8‐BrcGMP and dbcGMP increased LPS‐stimulated TNF‐ α synthesis but had no effect on KC TNF‐ α in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide‐releasing substance that stimulates guanylate cyclase, increased TNF‐ α synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF‐ α synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS‐induced KC TNF‐ α synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli. J. Leukoc. Biol. 57: 297–302; 1995.