Increased heat shock protein 90 (hsp90) expression leads to increased apoptosis in the monoblastoid cell line U937 following induction with TNF-alpha and cycloheximide: a possible role in immunopathology.
In this study, we examined the hypothesis that heat shock proteins (hsp) (such as hsp72 and hsp90) are implicated in the regulation of forms of cell injury that lead to programmed cell death. The monoblastoid cell line U937 has been used as a model system. For hsp90, which is not heat inducible in this cell line, we used stable U937 transfectants that either hyperexpress or hypoexpress the protein. For hsp72 (which is reproducibly induced in all three cell lines to relatively high levels of expression), we studied U937 cells before and after heat shock. We showed that apoptosis does occur in the monoblast/mononuclear phagocyte lineage, and that it could be induced in vitro by serum deprivation, UV light, or TNF-alpha in combination with cycloheximide (cx). However, an excess of hsp90 is associated with increased apoptosis when the cells are treated with a combination of TNF-alpha and cx but not when they are exposed to UV B radiation. This was complemented by the finding that reduced hsp90 levels correlate with protection against apoptosis in the TNF-alpha- and cx-treated cells. Furthermore, new synthesis of hsp72 does not protect against apoptosis. Thus, hsp90 levels may play a role in controlling the part played by mononuclear phagocytes in immunopathology.
Department of Immunology, University College London Medical School, United Kingdom.
J
J
Galea-Lauri
A J
AJ
Richardson
D S
DS
Latchman
D R
DR
Katz
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014466:Ultraviolet Rays
D015703:Antigens, CD; D016895:Culture Media, Serum-Free; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide