IL-12 decreases activation-induced cell death in human naive Th cells costimulated by intercellular adhesion molecule-1. I. IL-12 alters caspase processing and inhibits enzyme function.
Th cells can receive costimulatory signals through the LFA-1/ICAM-1 accessory pathway that are sufficient to induce early Th cell proliferation, but not subsequent cell expansion and maintenance of cell viability. To investigate the regulatory role for IL-12 in ICAM-1-mediated costimulation, human naive Th cells were stimulated with coimmobilized anti-CD3 mAb and ICAM-1 Ig in the presence or absence of IL-12. The ICAM-1-mediated costimulatory signals in this model resulted in early Th cell proliferation followed by cell death that was partially mediated by Fas and involved loss of mitochondrial membrane potential, processing of procaspase-9 and -3, and activation of caspase-3. Addition of IL-12 prevented activation-induced cell death and promoted late proliferation. ICAM-1 + IL-12-costimulated Th cells were resistant to Fas-mediated cell death through a mechanism that did not appear to involve a decrease in either Fas or Fas ligand expression. IL-12 did not inhibit the loss of mitochondrial membrane potential induced by ICAM-1-mediated costimulation, and this finding was consistent with the inability of IL-12 to increase expression of the antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-x(L). Interestingly, IL-12 promoted an altered processing of procaspase-9 and -3 and a decrease in the percentage of cells displaying caspase-3 catalytic function. In conclusion, we now describe a novel regulatory function for IL-12 in preventing Th cell death and, as a result, in greatly increasing Th cell viability and expansion. Together, our findings indicate that IL-12 may perform this regulatory role by preventing Fas-mediated activation-induced cell death through inhibition of caspase-3 enzyme activity.
Palmer
E M
EM
Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Farrokh-Siar
L
L
Maguire van Seventer
J
J
van Seventer
G A
GA
D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002384:Catalysis; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D004357:Drug Synergism; D004792:Enzyme Precursors / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D007399:Interphase / Q000276:immunology; D007425:Intracellular Membranes / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008564:Membrane Potentials / Q000276:immunology; D008928:Mitochondria / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D061945:Caspase Inhibitors; D004792:Enzyme Precursors; D006131:Growth Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases