Genetic deletion of the tumor necrosis factor receptor p60 or p80 sensitizes macrophages to lipopolysaccharide-induced nuclear factor-kappa B, mitogen-activated protein kinases, and apoptosis.
Whether deletion of tumor necrosis factor (TNF) receptor 1 or 2 affects lipopolysaccharide (LPS)-mediated signaling is not understood. In this report, we used macrophages derived from wild type (wt) mice and from mice null for the type 1 receptor (p60-/-), the type 2 receptor (p80-/-), or both (p60-/- p80-/-) to investigate the effect of these receptors on LPS-mediated activation of NF-kappaB, mitogen-activated protein kinases, and apoptosis. LPS activated NF-kappaB by 3-4-fold in wt cells but by 9-10-fold in p60-/-, p80-/-, and p60-/- p80-/- macrophages. These results correlated with the IkappaBalpha kinase activation, which is needed for NF-kappaB activation. LPS-induced cyclooxygenase-2 and inducible NO synthase proteins and NO production were maximum in p60-/- p80-/- macrophages and minimum in wt cells. LPS activated C-Jun N-terminal kinase, p38MAPK, and extracellular signal-regulated kinase in wt cells, but the levels were much higher in p60-/-, p80-/-, and p60-/- p80-/- cells. LPS-induced cytotoxicity, poly(ADP-ribose) polymerase cleavage, and annexin V staining were also highest in p60-/- p80-/- cells and lowest in wt cells. The difference in LPS signaling was unrelated to the expression of LPS receptors, CD14, or toll-like receptor 4. Overall, our studies indicate that deletion of either of the TNF receptors sensitizes the macrophages to LPS and provide evidence for cross-talk between TNF and LPS signaling.
Takada
Yasunari
Y
Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Aggarwal
Bharat B
BB
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D020239:Receptor Cross-Talk; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction
D015703:Antigens, CD; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases