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Biochim Biophys Acta. 1999 Jun 8;1450(2):130-44.

Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-kappaB cascades, but not lipopolysaccharide-incorporation steps.

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Department of Microbiology, Jichi Medical School, Tochigi-ken 329-0498, Japan.


Endotoxin/lipopolysaccharide (LPS) tolerance, a hyporesponsive state to endotoxin or LPS stimulation, was induced in murine peritoneal macrophages by previous exposure of macrophages to LPS. Expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNA in response to LPS stimulation was suppressed in LPS-tolerant macrophages. Tyrosine phosphorylations in response to LPS of 40-45-kDa proteins in non-tolerant macrophages were also suppressed in LPS-tolerant macrophages. These proteins corresponded to two members of the mitogen-activated protein kinase (MAPK) family, ERK and p38. In addition to these proteins, another MAPK family protein, JNK, was also suppressed in LPS-tolerant macrophages. Activation of Raf-1, located in the upstream portion of ERK cascades, was also suppressed by LPS-tolerance induction. These suppressions in LPS-tolerant macrophages were exhibited against stimulation by an LPS agonist like taxol, but not towards stimulation by an unrelated activator like phorbol ester (PMA). Activation of the transcription factor NF-kappaB, which is supposed to be one of the components of another important pathway for transduction of LPS-stimulated cytokine producing signals, was strongly suppressed and degradation of IkappaB, an inhibitor of NF-kappaB, was also severely diminished in LPS-tolerant macrophages. Although a monosaccharide lipid A analog, GLA-58, was able to stimulate macrophages to activate ERK proteins without cytokine production, pretreatment of macrophages with this compound suppressed both LPS-stimulated activation of ERK and cytokine production. Furthermore, downregulation of LPS-uptake in LPS-tolerant macrophages was not observed. Based on all these findings, LPS tolerance might be caused by the previous activation of some components on LPS-signaling pathways. This may then induce a refractory state in key LPS-signal transducer molecules located downstream of the cell membrane LPS receptor and upstream of the branching point in intracellular cascades for activation of MAPK and NF-kappaB, probably in some initial steps of intracellular signaling.

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