Persistence of calcium elevation in the HPB-ALL human T cell line correlates with immunosuppressive properties of polycyclic aromatic hydrocarbons.
The immunosuppressive synthetic methylated polycyclic aromatic hydrocarbon (PAH), 7,12-dimethylbenz[a]anthracene (DMBA), has been shown to cause both an immediate and a sustained elevation of free intracellular calcium (Ca2+) in human T cells. In the present studies, a series of anthracene- and pyrene-based PAHs were tested for rapid (3 min) and sustained (4 hr) Ca2+ mobilization in the HPB-ALL human T cell line measured by flow cytometry using Fluo-3 as a Ca2+ indicator. Immunosuppressive PAHs produced a sustained Ca2+ elevation for at least 4 hr, while weakly immunosuppressive PAHs caused only a transient increase in Ca2+. The immunosuppressive PAHs, DMBA, benzo[a]pyrene, dibenz[a,h]anthracene, and 9,10-dimethylanthracene, produced a sustained increase in intracellular Ca2+ in HPB-ALL cells. Those PAHs with moderate to minimal immunosuppressive properties (i.e., dibenz[a,c]anthracene, benz[a]anthracene, benzo[e]pyrene, and anthracene) produced small and transient Ca2+ mobilization responses in HPB-ALL cells. It appeared that methylation of anthracene at the 9,10-positions increased the duration of Ca2+ mobilization, whereas the addition of a benzene group in the "a" position was associated with a transient increase in Ca2+ levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, partially inhibited the rapid and sustained PAH-induced Ca2+ mobilization responses, while the protein kinase C (PKC) inhibitors, staurosporine and calphostin C, had essentially no effect on PAH-induced Ca2+ elevation. It appears that the action of PAHs on PTKs is important in the rapid Ca2+ response of human T cells. However, additional biochemical mechanisms appear to be responsible for the sustained elevation of Ca2+ produced by PAHs in T cells. The results of these studies demonstrate that persistent elevation of intracellular Ca2+ by PAHs correlates with their known immunosuppressive properties.
Krieger
J A
JA
University of New Mexico College of Pharmacy, Toxicology Program, Albuquerque 87131.
Born
J L
JL
Burchiel
S W
SW
D001564:Benzo(a)pyrene / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D004789:Enzyme Activation; D019833:Genistein; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007424:Intracellular Fluid / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D011083:Polycyclic Compounds / Q000633:toxicity*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D007529:Isoflavones; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium