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

Endotoxin [lipopolysaccharide (LPS)] tolerance suppresses macrophage/monocyte proinflammatory-mediator production. This phenomenon also confers cross-tolerance to other stimuli including tumor necrosis factor (TNF) a and interleukin (IL)-1 beta. Post-receptor convergence of signal transduction pathways might occur after LPS, IL-1 beta, and TNF-alpha stimulation. Therefore, it was hypothesized that down-regulation of common signaling 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 kappaB alpha (I kappaB alpha) DNA binding of nuclear factor-kappaB (NF kappaB), and mediator production were examined. In naive cells, LPS, TNF-alpha, and IL-1 beta induced I kappaB alpha degradation, kinase phosphorylation, and NF-KB DNA binding. LPS stimulation induced production of TNF-alpha or TxB(2) and degradation of IRAK. However, neither TNF-alpha nor IL-1 beta induced IRAK degradation or stimulated TNF-alpha or TxB(2) production in naive cells. Pretreatment with each stimulus induced homologous tolerance to restimulation with the same agonist. LPS tolerance also suppressed LPS-induced TxB(2) and TNF-alpha production. LPS pretreatment induced cross-tolerance to TNF-alpha or IL-1 beta stimulation. Pretreatment with TNF-alpha induced cross-tolerance to LPS-induced signaling events and TxB(2) production. Although pretreatment with IL-1 beta did not induce cross-tolerance to LPS-induced signaling events, it strongly inhibited LPS TNF-alpha and TxB(2) production. These data demonstrate that IL-1 beta induces cross-tolerance to LPS-induced mediator production without suppressing LPS-induced signaling to MAP kinases or NF-KB activation.