Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment.
Estrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17beta-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca(2+) increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.
Subramanian
Manikandan
M
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
Shaha
Chandrima
C
D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003600:Cytosol / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004958:Estradiol / Q000276:immunology* / Q000494:pharmacology; D004967:Estrogens / Q000276:immunology / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000276:immunology; D012727:Sex Characteristics; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000276:immunology* / Q000378:metabolism
C494826:BAX protein, human; D004967:Estrogens; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D004958:Estradiol; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium