Lipopolysaccharide- and paclitaxel (Taxol)-induced tolerance in murine peritoneal macrophages

Abstract

LPS-tolerance, a state of refractoriness to LPS-stimulation, is induced in murine peritoneal macrophages by prior exposure to LPS. LPS-induced expression of TNF and IL-6 mRNA as well as activation of various intracellular kinases and factors, including ERK, p38, JNK, Raf-1 and NF-κB were all suppressed in LPS-tolerant macrophages; responses to stimulation by paclitaxel (Taxol™), an LPS agonist, were similarly suppressed, but responses to phorbol esters (PMA) were unaffected. Binding and uptake of [¹²⁵I]-labeled LPS to tolerant macrophages was somewhat greater in tolerant than in non-tolerant macrophages. Thus, the refractory state appears to involve inhibition or blockade of LPS-signaling molecules located downstream of the cell membrane LPS receptor and upstream of the branch point in the intracellular cascades leading to activation of MAPK and NFκB. LPS conditioning also suppressed LPS- and Taxol-induced TNF production, but augmented nitric oxide (NO) production. In contrast, Taxol conditioning failed to suppress LPS-induced TNF production. Conditioning with the synthetic taxoid analog, nor-seco-taxoid, which does not induce macrophage activation, enhanced LPS- and Taxol-induced NO production. These findings provide us with new information about the relationship between the LPS and Taxol receptors as well as about the signaling pathways leading to TNF and NO production.

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