Differential role of calcium in tumour necrosis factor-mediated apoptosis and secretion of granulocyte-macrophage colony-stimulating factor in a T cell hybridoma.
The authors investigated the dependence on extracellular and intracellular free Ca2+ in the induction of apoptosis and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) by tumour necrosis factor (TNF) in a rat/mouse T cell hybridoma PC60 R55/R75, using the Ca2+ chelators EGTA and BAPTA/AM, respectively. TNF-induced apoptosis still occurred in the absence of free Ca2+, while GM-CSF production required the continuous presence of Ca2+. The latter was also true for GM-CSF production driven by interleukin 1 (IL-1). The dependence on Ca2+ in the induction of GM-CSF, but not of apoptosis, was further confirmed by the inhibition of TNF- or IL-1-induced cytokine production by cyclosporin A or FK506, drugs that block the Ca2+/calmodulin-dependent protein Ser/Thr phosphatase calcineurin. This differential requirement for Ca2+ illustrates the partial functional redundancy between TNF and IL-1, showing the activation of cytokine gene expression through a Ca(2+)-dependent activation of calcineurin, and a Ca(2+)-independent activation of apoptosis, exerted solely by TNF.
Denecker
G
G
Laboratory of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium.
Vandenabeele
P
P
Grooten
J
J
Penning
L C
LC
Declercq
W
W
Beyaert
R
R
Buurman
W A
WA
Fiers
W
W
D000818:Animals; D017209:Apoptosis; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D002712:Chlorides / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006825:Hybridomas / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D017967:Zinc Compounds / Q000494:pharmacology
D002712:Chlorides; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D017967:Zinc Compounds; D001312:Aurintricarboxylic Acid; D004533:Egtazic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; C016837:zinc chloride; D019703:Calcineurin; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D016559:Tacrolimus