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Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages.

ABSTRACT: Metallothionein (MT) is a low-molecular-mass, cysteine-rich metal binding protein thought to be involved in the detoxification of heavy metals and scavenging of free radicals. MT is directly induced not only by heavy metals, but also by hormones and cytokines. The present study, which uses mice with genetic deletions of the MT proteins (MT(-/-) mice), was designed to evaluate the effects of MT on the expression of pro-inflammatory cytokines in macrophages. We found that the production of tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS) in peritoneal macrophages is up-regulated by MT via the modulation of nuclear factor kappaB (NF-kappaB) activity. This conclusion is supported by the following observations: (1) LPS stimulated the secretion of less TNF activity from MT(-/-) peritoneal exudate macrophages (PEMs) than from wild-type controls (MT(+/+) mice) without a difference in the pattern of kinetics; (2) LPS-stimulated expression of TNF-alpha mRNA was decreased in MT(-/-) PEMs; (3) LPS-stimulated activation of NF-kappaB was decreased in MT(-/-) PEMs; and (4) production of TNF in PEMs of MT(-/-) mice after LPS treatment in vivo was decreased (compared with MT(+/+) PEMs). Expression of other inflammatory cytokines, interleukin (IL)-1alpha and IL-6 mRNA, which were modulated by NF-kappaB, were also down-regulated in MT(-/-) PEMs. Thus MT plays a key role in the LPS-induced activation of PEMs via the modulation of NF-kappaB activity.

SUBMITTER: Kanekiyo M

PROVIDER: S-EPMC1222316 | biostudies-other | 2002 Jan

REPOSITORIES: biostudies-other

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Project description:Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM?) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM? or bone marrow-derived macrophages (BMM?) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice. We found that CCR8-/- PM? demonstrated attenuated secretion of tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM? but not BMM?. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM? aggregation. Similar to CCR8-/- PM?, R243 attenuated secretion of TNF-?, IL-6, and most strikingly IL-10 from WT PM?, but not BMM?. CCR8-/- PM? and R243-treated WT PM? both showed suppressed c-jun N-terminal kinase activity and nuclear factor-?B signaling after LPS treatment when compared with WT PM?. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8-/- mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PM?. Through use of CCR8-/- mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

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Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages.

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