Potentiation of apoptosis by heat stress plus pesticide exposure in stress resistant human B-lymphoma cells and its attenuation through interaction with follicular dendritic cells: role for c-Jun N-terminal kinase signaling.
B lymphocytes (B cells) become increasingly resistant to apoptosis induction during their differentiation in the microenvironment of the germinal center of lymphoid follicles. This is due to increases in the levels of Bcl-2 protein as well as survival signals generated through B-cell binding to follicular dendritic cells (FDC). However, it is not known whether this cellular resistance may be bypassed as a result of exposure to multiple environmental stress factors resulting in excessive apoptosis induction in B cells. We examined this question of whether apoptosis may be induced, and possibly potentiated, as a result of exposure of the human EW36 B-lineage cell line, having elevated Bcl-2 protein, to heat stress and pesticide combination exposures in a co-culture system with a human FDC cell line. This co-culture system recapitulates essential features of a human germinal center including adherence of B cells to FDC generating survival signals. We found that heat stress plus pesticide exposures resulted in substantial potentiation of apoptosis in EW36 cells, effectively bypassing their stress resistance. Similar results were obtained when paraquat was substituted for heat stress. Furthermore, the JNK pathway was activated by some combination exposures, such as heat stress plus antimycin A, but this pathway was found to play a cytoprotective role in EW36 cells. Importantly, EW36 cell binding to FDC reduced the extent of apoptosis induction by most combination exposures. These results reveal cell stress scenarios that can greatly augment apoptosis in stress-resistant human B-cells and a germinal center interaction that selectively attenuates pesticide-induced apoptosis.
Bloom
Stephen E
SE
Department of Microbiology and Immunology, Veterinary Medical Center, Cornell University, Ithaca, New York 14853, USA. seb14@cornell.edu
Lemley
Ann T
AT
Muscarella
Donna E
DE
D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D020566:Dendritic Cells, Follicular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D018882:Heat Stress Disorders; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology; D006358:Hot Temperature; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
D007306:Insecticides; D019253:Proto-Oncogene Proteins c-bcl-2; D048031:JNK Mitogen-Activated Protein Kinases