Involvement of the lymphocytic muscarinic acetylcholine receptor in methylmercury-induced c-Fos expression and apoptosis in human leukemic T cells.
Methylmercury (MeHg) is an environmental toxicant that is known to induce lymphocyte apoptosis; however, little is known about the molecular mechanism involved. Data showed that MOLT-3 cells were more sensitive to MeHg-induced cytotoxic effects than Jurkat clone E6-1 cells, suggesting that the lymphocytic muscarinic cholinergic system may be involved since the expressions of five subtypes (M1-M5) of muscarinic acetylcholine receptor (mAChR) in MOLT-3 cells are higher than in Jurkat cells. The role of mAChR-linked pathways in MeHg-induced apoptosis in human leukemic T cells was examined in this study. Treatment of the MOLT-3 cells with 1 microM MeHg produced induction of c-Fos expression, apoptotic cell death, and downregulation of mAChR. MeHg-induced c-Fos expression was significantly reduced by pretreatment with atropine (a nonselective mAChR antagonist), or 4-DAMP (a selective M1/M3 mAChR antagonist), whereas pirenzipine (a selective M1 mAChR antagonist) or himbazine (a selective M2/M4 mAChR antagonist) did not reduce this induction, suggesting that MeHg-induced c-Fos expression through the activation of the mAChR, at least M3 subtype, is involved. Pretreatment with 4-DAMP or SB 203580 (a specific p38 inhibitor) resulted in decreases in the level of phosphorylated p38, c-Fos expression, and apoptotic cell death induced by MeHg. Taken together, these data suggest that the mAChR-p38-dependent pathway participates in the increase of c-Fos expression, which is involved in MeHg-induced lymphocyte apoptosis. In addition, a noncytotoxic concentration of MeHg (0.1 microM) inhibited PHA/PMA-stimulated interleukin (IL)-2 production, and this inhibition was reversed by pretreatment with atropine or 4-DAMP. Overall, this study provides initial evidence that MeHg may alter the immune system by targeting the lymphocytic mAChR.
Suriyo
Tawit
T
Inter-University Program in Environmental Toxicology, Technology and Management, Asian Institute of Technology, Mahidol University and Chulabhorn Research Institute, Bangkok.
Thiantanawat
Apinya
A
Chaiyaroj
Sansanee C
SC
Parkpian
Preeda
P
Satayavivad
Jutamaad
J
D017209:Apoptosis / Q000187:drug effects*; D004347:Drug Interactions; D016762:Genes, fos / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D008767:Methylmercury Compounds / Q000633:toxicity*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D008767:Methylmercury Compounds; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C004925:methylmercuric chloride