Zinc chelators inhibit eotaxin, RANTES, and MCP-1 production in stimulated human airway epithelium and fibroblasts.
Asthma is characterized by an increased production of eosinophil-active C-C chemokines by the airway epithelium. Recent studies have identified the presence of important quantities of labile zinc in the conducting airways. We hypothesized that modulation of this labile zinc could influence the production of proinflammatory chemokines in respiratory epithelial cells. The zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and the heavy metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS) were used to reduce the labile zinc content of A549, BEAS-2B, and HFL-1 cells. Northern blot analysis and RNase protection assay were used to study the effects of the zinc chelators on mRNA expression. DMPS and TPEN specifically inhibited the production of eotaxin, regulated on activation, normal T-cell expressed, and presumably secreted, and monocyte chemotactic protein-1 in TNF-alpha-stimulated respiratory epithelial cells and fibroblasts through labile zinc chelation. The inhibitory effects of DMPS and TPEN were associated with the decreased binding of the zinc-finger transcription factor GATA-1, whereas no change in NF-kappaB activation was observed. Together these results demonstrate that modulation of the labile pool of zinc can regulate gene expression and protein synthesis of C-C chemokines in lung epithelial cells and fibroblasts.
Richter
Martin
M
Unité de recherche pulmonaire, Faculté de médecine, Université de Sherbrooke, 3001 12e Ave. Nord, Sherbrooke, QC, Canada J1H 5N4. Pierre.Larivee@USherbrooke.ca
Cantin
André M
AM
Beaulieu
Claudia
C
Cloutier
Alexandre
A
Larivée
Pierre
P
D001249:Asthma / Q000276:immunology; D002614:Chelating Agents / Q000494:pharmacology*; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000235:genetics*; D018946:Chemokine CCL5 / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005029:Ethylenediamines / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D050982:GATA1 Transcription Factor; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014494:Unithiol / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
C515456:CCL11 protein, human; D002614:Chelating Agents; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D005029:Ethylenediamines; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D014494:Unithiol; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine