Modulation of endotoxin-induced NF-κB activation in lung and liver through TNF type 1 and IL-1 receptors

We investigated the requirement for tumor necrosis factor-α (TNF-α) and interleukin (IL)-1 receptors in the pathogenesis of the pulmonary and hepatic responses to Escherichia coli lipopolysaccharide (LPS) by studying wild-type mice and mice deficient in TNF type 1 receptor [TNFR1 knockout (KO)] or both TNF type 1 and IL-1 receptors (TNFR1/IL-1R KO). In lung tissue, NF-κB activation was similar among the groups after exposure to aerosolized LPS. After intraperitoneal injection of LPS, NF-κB activation in liver was attenuated in TNFR1 KO mice and further diminished in TNFR1/IL-1R KO mice; however, in lung tissue, no impairment in NF-κB activation was found in TNFR1 KO mice and only a modest decrease was found in TNFR1/IL-1R KO mice. Lung concentrations of KC and macrophage-inflammatory peptide 2 were lower in TNFR1 KO and TNFR1/IL-1R KO mice after aerosolized and intraperitoneal LPS. We conclude that LPS-induced NF-κB activation in liver is mediated through TNF-α- and IL-1 receptor-dependent pathways, but, in the lung, LPS-induced NF-κB activation is largely independent of these receptors.