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.
Department of Surgery, University of Pittsburgh, Pennsylvania.
B G
BG
Harbrecht
S C
SC
Wang
R L
RL
Simmons
T R
TR
Billiar
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