title: Differential regulation of TLR-dependent MyD88 and TRIF signaling pathways by free zinc ions.
abstract: Zinc signals are utilized by several immune cell receptors. One is TLR4, which causes an increase of free zinc ions (Zn(2+)) that is required for the MyD88-dependent expression of inflammatory cytokines. This study investigates the role of Zn(2+) on Toll/IL-1R domain-containing adapter inducing IFN-β (TRIF)-dependent signals, the other major intracellular pathway activated by TLR4. Chelation of Zn(2+) with the membrane-permeable chelator N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine augmented TLR4-mediated production of IFN-β and subsequent synthesis of inducible NO synthase and production of NO. The effect is based on Zn(2+) acting as a negative regulator of the TRIF pathway via reducing IFN regulatory factor 3 activation. This was also observed with TLR3, the only TLR that signals exclusively via TRIF, but not MyD88, and does not trigger a zinc signal. In contrast, IFN-γ-induced NO production was unaffected by N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine. Taken together, Zn(2+) is specifically involved in TLR signaling, where it differentially regulates MyD88 and TRIF signaling via a zinc signal or via basal Zn(2+) levels, respectively.
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Brieger
authors.forename: Lothar
authors.initials: L
authors.lastname: Rink
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011137:Polystyrenes / Q000494:pharmacology; D011145:Polyvinyls / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology; D015032:Zinc / Q000494:pharmacology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D016207:Cytokines; D005029:Ethylenediamines; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D011137:Polystyrenes; D011145:Polyvinyls; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015032:Zinc; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C006960:chelex; C496317:Nos2 protein, mouse; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine