Involvement of the Lymphocytic Muscarinic Acetylcholine Receptor in Methylmercury-Induced c-Fos Expression and Apoptosis in Human Leukemic T Cells

• Published in: Journal of Toxicology and Environmental Health, Part A Part A, 2008-01, Vol.71 (16), p.1109-1123
• Main Authors: Suriyo, Tawit, Thiantanawat, Apinya, Chaiyaroj, Sansanee C., Parkpian, Preeda, Satayavivad, Jutamaad
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Drug Interactions; Genes, fos - drug effects; Humans; Jurkat Cells; Methylmercury Compounds - toxicity; Muscarinic Antagonists - pharmacology; Piperidines - pharmacology; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tumor Cells, Cultured
• ISSN: 1528-7394; 1087-2620
• DOI: 10.1080/15287390802114725

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 μM 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 μM) 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.