Mercury inhibition of neutrophil activity: evidence of aberrant cellular signalling and incoherent cellular metabolism.
Exposure to environmental heavy metals has been reported to affect the immune system. Here, we tested the hypothesis that Hg(+2), acting through membrane proteins, disrupts metabolic dynamics and downstream cell functions in human neutrophils. We found that HgCl(2) inhibited: (1) polarization and (2) immunoglobulin (Ig)G-mediated phagocytosis of sheep erythrocytes in a dose-dependent manner from 2.5 to 10 microM. Because these activities have been linked with pro-inflammatory signalling, we also studied the effects of HgCl(2) on intracellular signalling by measuring protein tyrosine phosphorylation. HgCl(2) at doses = 1 microM increased tyrosine phosphorylation. We also studied the effect of HgCl(2) on neutrophil metabolism by measuring NAD(P)H autofluorescence as an indicator of intracellular NAD(P)H concentration. After HgCl(2) treatment, we found that normal sinusoidal NAD(P)H oscillations became incoherent. We recently reported that the NAD(P)H oscillation frequency is affected by cell migration and activation, which can in turn be regulated by integrin-mediated signalling. Therefore, we examined the effects of HgCl(2) on cell surface distribution of membrane proteins. After exposure to environmentally relevant concentrations of HgCl(2) we found that CR3, but not other membrane proteins (e.g. uPAR, Fc gamma RIIA and the formyl peptide receptor), became clustered on cell surfaces. We suggest that HgCl2 disrupts integrin signalling/functional pathways in neutrophils.
Worth
R G
RG
Department of Biological Sciences, Wayne State University, Detroit, MI 48201, USA.
Esper
R M
RM
Warra
N S
NS
Kindzelskii
A L
AL
Rosenspire
A L
AL
Todd
R F
RF
Petty
H R
HR
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D003864:Depression, Chemical; D004306:Dose-Response Relationship, Immunologic; D004912:Erythrocytes; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016023:Integrins / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects; D008627:Mercuric Chloride / Q000494:pharmacology* / Q000633:toxicity; D008954:Models, Biological; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011940:Receptor Aggregation / Q000187:drug effects; D017452:Receptors, IgG / Q000187:drug effects; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects*
D007074:Immunoglobulin G; D016023:Integrins; D008565:Membrane Proteins; D017452:Receptors, IgG; D009249:NADP; D008627:Mercuric Chloride; D009240:N-Formylmethionine Leucyl-Phenylalanine