Selective role of intracellular chloride in the regulation of the intrinsic but not extrinsic pathway of apoptosis in Jurkat T-cells.
Apoptosis is a genetic program for the removal of unwanted cells from an organism, which is distinct from necrosis by its characteristic volume loss or apoptotic volume decrease. This cell shrinkage is the result of ion redistribution that is crucial for both the activation and execution of apoptosis. Here we report that UV-C but not Fas ligand treatment results in a significant decrease in intracellular chloride that can be abolished by modulation of chloride flux using either the chloride channel inhibitor SITS or medium with a reduced chloride concentration. Accordingly, downstream events are diminished during UV-C-induced apoptosis following chloride flux modulation, whereas Fas ligand-induced apoptotic characteristics are not affected. Moreover, the activation of the mitogen-activated protein kinase signal transduction pathway early in the apoptotic signaling cascade was affected by chloride flux in Jurkat T-cells. Thus, an alteration of intracellular chloride plays an important role in the activation of signaling molecules upstream of the mitochondria, specifically impairing the intrinsic but not extrinsic apoptotic pathway.
Heimlich
Gerd
G
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC 27709, USA.
Cidlowski
John A
JA
D017209:Apoptosis; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007477:Ions; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D011188:Potassium / Q000737:chemistry; D015398:Signal Transduction; D012964:Sodium / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D014466:Ultraviolet Rays
D002712:Chlorides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007477:Ions; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D045304:Cytochromes c; D012964:Sodium; D011188:Potassium