Fluoranthene-induced apoptosis in murine T cell hybridomas is independent of the aromatic hydrocarbon receptor.
Recent studies suggest that environmental chemicals such as polycyclic aromatic hydrocarbons (PAH) compromise the immune system in part through the induction of programmed cell death (apoptosis). Nevertheless, mechanisms through which PAH induce apoptosis remain elusive. In particular, the role of the 8S AhR remains controversial and the nature of intracellular signal transduction in PAH-induced apoptosis remains largely undefined. To extend previous studies to the T cell compartment and to develop a clonal system in which intracellular signals leading to PAH-induced apoptosis can be dissected, the ability of fluoranthene, a ubiquitous, but less well-studied PAH, to induce apoptosis in murine T cell hybridomas was evaluated. Particular emphasis was placed on the role of the 8S AhR. The data indicate that (1) three of four hybridomas studied undergo apoptosis within 8 hr of fluoranthene exposure; (2) fluoranthene induces growth arrest concurrent with apoptosis; (3) at doses sufficient to induce lymphocyte apoptosis, fluoranthene does not induce AhR nuclear translocation in cells expressing high AhR levels; (4) fluoranthene-responsive hybridomas do not express AhR mRNA or protein; (5) the Ca2+ chelating agent EGTA partially inhibits fluoranthene-induced apoptosis. These results (1) indicate the immunosuppressive potential of fluoranthene; (2) support a role for apoptosis in PAH immunotoxicity; (3) demonstrate that fluoranthene-mediated T cell death and growth arrest are AhR independent; and (4) illustrate similarities between PAH- and antigen-specific receptor-mediated apoptosis. These findings encourage consideration of AhR- independent events in PAH risk assessment.
Yamaguchi
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Department of Environmental Health, Boston University Schools of Medicine and Public Health, Massachusetts 02118, USA.
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004533:Egtazic Acid / Q000494:pharmacology; D005449:Fluorenes / Q000633:toxicity*; D006825:Hybridomas / Q000166:cytology* / Q000187:drug effects; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013050:Spectrometry, Fluorescence; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology
D002614:Chelating Agents; D017931:DNA Primers; D005449:Fluorenes; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C007738:fluoranthene; D004533:Egtazic Acid; D004247:DNA; D002118:Calcium