Effect of cross-tolerance between endotoxin and TNF-� or IL-1� on cellular signaling and mediator production

tolerance suppresses macrophage/monocyte proin-flammatory-mediator production. This phenome-non also confers cross-tolerance to other stimuli including tumor necrosis factor (TNF) a and inter-leukin (IL)-1b. Post-receptor convergence of sig-nal transduction pathways might occur after LPS, IL-1b, and TNF-a stimulation. Therefore, it was hypothesized that down-regulation of common sig-naling molecules induces cross-tolerance among these stimuli. LPS tolerance and cross-tolerance were examined in THP-1 cells. Phosphorylation of MAP kinases and degradation of inhibitor kBa (IkBa) DNA binding of nuclear factor-kB (NF-kB), and mediator production were examined. In naive cells, LPS, TNF-a, and IL-1b induced IkBa degradation, kinase phosphorylation, and NF-kB DNA binding. LPS stimulation induced production of TNF-a or TxB2 and degradation of IRAK. How-ever, neither TNF-a nor IL-1b induced IRAK deg-radation or stimulated TNF-a or TxB2 production in naive cells. Pretreatment with each stimulus in-duced homologous tolerance to restimulation with the same agonist. LPS tolerance also suppressed LPS-induced TxB2 and TNF-a production. LPS pretreatment induced cross-tolerance to TNF-a or IL-1b stimulation. Pretreatment with TNF-a in-duced cross-tolerance to LPS-induced signaling events and TxB2 production. Although pretreat-ment with IL-1b did not induce cross-tolerance to LPS-induced signaling events, it strongly inhibited LPS TNF-a and TxB2 production. These data dem-onstrate that IL-1b induces cross-tolerance to LPS-induced mediator production without sup-pressing LPS-induced signaling to MAP kinases o