Involvement of nuclear factor-kappa B in platelet-activating factor-mediated tumor necrosis factor-alpha expression.
Tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) are important mediators of inflammatory reactions, and their release is controlled by a positive feedback network. However, the regulatory mechanisms underlying the interaction of these two molecules are unknown. Within 10 min of the injection of lipopolysaccharide (LPS) into C57BL/6 mice, effects inducible by PAF such as anaphylactic shock-like symptoms, disseminated intravascular coagulation, and hemorrhage in renal medullae were observed, and all these pathological changes were prevented by the PAF antagonist, BN 50739. The plasma level of PAF after LPS injection reached a peak at 5 min. TNF-alpha gene expression was evident 20 min after LPS injection and was maximal at 40 min, and the level of serum TNF-alpha reached a peak at 1 h. Pretreatment with BN 50739 inhibited LPS-induced TNF-alpha gene expression and protein synthesis in a dose-dependent manner. Injection of PAF or treatment of the macrophage cell line, J774A.1, with PAF activated the transcription factor, nuclear factor (NF)-kappa B, which is essential for inducible TNF-alpha transcription. The activation of NF-kappa B by PAF preceded the LPS-mediated TNF-alpha gene expression. Pretreatment with BN 50739 inhibited LPS-induced mobilization of NF-kappa B in a dose-dependent manner in vivo as well as in vitro. These data suggest that PAF, which is released immediately or shortly after LPS injection, induces the expression of TNF-alpha through the activation of NF-kappa B.
Im
S Y
SY
Department of Microbiology, College of Natural Sciences, Chonnam National University, Kwangju, Republic of Korea.
Han
S J
SJ
Ko
H M
HM
Choi
J H
JH
Chun
S B
SB
Lee
D G
DG
Ha
T Y
TY
Lee
H K
HK
D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010972:Platelet Activating Factor / Q000378:metabolism / Q000502:physiology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
D008070:Lipopolysaccharides; D016328:NF-kappa B; D010972:Platelet Activating Factor; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha