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 κB (NF-κB) activity. This conclusion is supported by the following observations : (1) LPS stimulated the secretion of less TNF activity from MT −/−

Peculiarities of the Molecular Structure and Functions of Metallothioneins in the Central Nervous System

“…A few studies suggest that MTs can be used as regulators of activation of NF-kB [5,66]. The authors cited confirmed that a directed interaction between MT and a р50-subunit of NF-kB results from activation of this factor.…”

Zinc homeostasis in pediatric critical illness*

“…Metallothioneins are the major intracellular zinc binding proteins and exist in various isoforms in humans. MT-1 and MT-2 are known to be involved in stress responses, being induced by glucocorticoids, heavy metals, and reactive oxygen species, as well as by zinc deficiency (9,10). Although MT-1 overexpression might be predicted to be protective, MT overexpressing mice were more sensitive to tumor necrosis factormediated lethality, and administration of zinc mitigated this sensitivity.…”

“…Intracellular and plasma zinc levels are regulated in part by MT (11). MT transcription is strongly down-regulated in the setting of zinc deficiency, but is up-regulated with inflammation, metals, and administration of exogenous glucocorticoids (9,10).…”

Zinc signals and immune function

“…Despite these efforts, zinc biology is still far from being completely understood; yet, we have now a better understanding of the chemical speciation of zinc in biological systems and enhanced knowledge regarding its interaction with proteins. In mammalian cells, the trace element zinc is exclusively present as the divalent cation (Zn 21 ), which does not undergo redox reactions at physiological redox potentials [9]. However, it is in some cases bound by oxidation sensitive ligands, namely cysteine thiols.…”

“…Zn 21 serves functions in catalysis or structural stabilization of over 300 enzymes and is a component of an even higher number of additional metalloproteins [11]. Many of those are found in immune cells, making a comprehensive summary of all zinc-dependent processes in the immune system virtually impossible.…”