Low and nontoxic inorganic mercury burdens attenuate BCR-mediated signal transduction.
The ubiquitous environmental heavy metal contaminant mercury (Hg) is a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease. However, the mechanism(s) whereby Hg initiates or perpetuates autoimmune responses, especially at the biochemical/molecular level, remain poorly understood. Recent work has established a relationship between impaired B-cell receptor (BCR) signal strength and autoimmune disease. In previous studies, we have shown that in mouse WEHI-231 B cells, noncytotoxic concentrations of inorganic mercury (Hg(+2)) interfered with BCR-mediated growth control, suggesting that BCR signal strength was impaired by Hg(+2). Extracellular signal-regulated kinase (ERK) 1,2 mitogen-activated protein kinase (MAPK) is responsible for the activation of several transcription factors in B cells. Phosphorylation of ERK serves as an essential node of signal integration for the BCR. Thus, the magnitude of ERK activation serves as an operational metric for BCR signal strength. Using Western blotting and phospho-specific flow cytometry, we now show that the kinetics and magnitude of BCR-mediated activation of ERK-MAPK are markedly attenuated in WEHI-231 cells and splenic B cells that have been exposed to low and nontoxic burdens of Hg(+2). However, Hg(+2) does not seem to act directly on ERK-MAPK but rather on an upstream element or elements of the BCR signal transduction pathway, above the level of the key protein tyrosine kinase Syk. Our data suggest that the site of action of Hg(+2) may very well be localized on the plasma membrane. These findings support a connection between Hg(+2) and attenuated BCR signal strength in the etiology of autoimmune disease.
McCabe
Michael J
MJ
Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.
Laiosa
Michael D
MD
Li
Li
L
Menard
Sherri L
SL
Mattingly
Raymond R
RR
Rosenspire
Allen J
AJ
D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008628:Mercury / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D008628:Mercury