Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis.
Tumor necrosis factor-alpha (TNF-alpha) 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-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF-alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha 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-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli.
Harbrecht
B G
BG
Department of Surgery, University of Pittsburgh, Pennsylvania.
Wang
S C
SC
Simmons
R L
RL
Billiar
T R
TR
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013189:SRS-A / Q000037:antagonists & inhibitors; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000634:Aminoquinolines; D008070:Lipopolysaccharides; D013189:SRS-A; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D003995:Dibutyryl Cyclic GMP; C041715:6-anilino-5,8-quinolinedione; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue