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. 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. Apoptosis or programmed cell death plays an important role in the removal of unwanted cells in multicellular organisms. An impaired or increased rate of apoptosis can lead to diseases such as cancer, neurodegeneration, AIDS, and autoimmune diseases. A typical morphological feature observed during apoptosis is the reduction of cellular volume (apoptotic volume decrease), a feature that distinguishes this form of cell death from necrosis (1Kerr J.F. Wyllie A.H. Currie A.R. Br. J. Cancer. 1972; 26: 239-257Crossref PubMed Scopus (12927) Google Scholar). Healthy cells maintain a constant cell size by keeping a delicate balance of their intracellular ions and osmolytes. Small variations in intracellular ionic composition in response to external osmolarity changes or cell cycle alterations are compensated via inherent volume-regulatory mechanisms (2Bortner C.D. Gomez-Angelats M. Cidlowski J.A. J. Biol. Chem. 2001; 276: 4304-4314Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 3Lang F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google Scholar, 4al-Habori M. Int. J. Biochem. 1994; 26: 319-334Crossref PubMed Scopus (42) Google Scholar). In order for cells to shrink during apoptosis, a significant loss of intracellular cations has been reported to occur (5Beauvais F. Michel L. Dubertret L. J. Leukocyte Biol. 1995; 57: 851-855Crossref PubMed Scopus (136) Google Scholar, 6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar, 8Nietsch H.H. Roe M.W. Fiekers J.F. Moore A.L. Lidofsky S.D. J. Biol. Chem. 2000; 275: 20556-20561Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 9Barbiero G. Duranti F. Bonelli G. Amenta J.S. Baccino F.M. Exp. Cell Res. 1995; 217: 410-418Crossref PubMed Scopus (141) Google Scholar). Furthermore, the physiological concentration of potassium in non-apoptotic cells has been shown to constrain the activation of caspases and to inhibit the activity of apoptotic nucleases (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar). Although the role of potassium and sodium during volume regulation and apoptotic volume decrease has been extensively studied (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 9Barbiero G. Duranti F. Bonelli G. Amenta J.S. Baccino F.M. Exp. Cell Res. 1995; 217: 410-418Crossref PubMed Scopus (141) Google Scholar), the function of the anion chloride is less well understood. Clearly, a flux of anions should occur in parallel with the loss of sodium or potassium to ensure electroneutrality. Along these lines, the involvement of a volume-sensitive outwardly rectifying chloride channel following several apoptotic Fas in Jurkat cells has been S. A. PubMed Scopus Google Scholar, I. Lepple-Wienhues A. M. Gulbins E. F. S. A. PubMed Scopus Google Scholar). In in a cell an of outwardly rectifying potassium was with a chloride following necrosis H.H. Roe M.W. Fiekers J.F. Moore A.L. Lidofsky S.D. J. Biol. Chem. 2000; 275: 20556-20561Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). channel been reported to both and necrosis apoptosis in and cells as well as E. A. S. A. 2000; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, A. S. M. Cell PubMed Scopus Google Scholar). of these the intracellular chloride concentration chloride to changes in intracellular such as sodium and which are for apoptotic volume decrease and the activation of downstream events such as and Furthermore, is of changes in ions such as chloride the signal transduction during apoptosis. In the we to the role of chloride ions early in the of apoptosis the intrinsic and extrinsic Fas apoptotic volume mitogen-activated protein sodium necrosis potassium pathway of apoptosis are not Bortner C.D. Cidlowski J.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Here we report using a medium with reduced chloride to the intracellular chloride as well as a chloride channel to chloride for the that UV-C but not treatment results in intracellular chloride decrease during apoptosis in Jurkat T-cells. Furthermore, we that chloride flux modulation is to intracellular sodium and potassium changes and that chloride ion flux specifically the UV-C activation of the kinase signaling cascade upstream of the and protein protein and from Cell and from and to was from was a concentration of in and not from and of the Cell and in medium with and was and which for of the chloride the chloride potassium and sodium to the by to medium was for using a modulation of chloride cells either with the chloride channel inhibitor SITS or in medium by for Apoptosis in Jurkat was by either of or treatment with UV-C in a UV-C the cells the for UV-C the of volume was constant to ensure an in of by intracellular chloride the was to the of the was reduced to the form with sodium as by the J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was in of in a of the to of cells a concentration of was by the was for to in the by a with cells a A was to the of cells with cell cells for in from to chloride and was as a for chloride in the to maintain A of the a in intracellular chloride concentration can be with to changes in the using the the of the the of intracellular Jurkat for in or medium by the of apoptosis. to by was to a concentration of in the of apoptotic and the was to the decrease in intracellular the from the and by intracellular sodium and potassium of or to of cells a concentration of was the cells for to the of to by was to a concentration of cells by of the cells either or and and using an and of the of changes in by F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google was to the of a F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google to of cells a concentration of was the cells for to by was to a concentration of cells using a and with an and and for F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google and of by apoptosis and with by using a protein of was using a protein of in the was with a Cell by apoptosis and with in of sodium and of inhibitor using a and for the protein was using a protein and the Cell for by apoptosis and with in of sodium and of inhibitor by for protein was using a protein and the by or of in with and for by V. and for following with with the by and for with to apoptotic in or chloride reduced and to apoptosis. a an in was to the and using the from the as the and the as the a was for the for was for by of cells of apoptosis. cells by the of of and the cells in and in of in for in the cells by using a by a of was by the of cells with by the of by the of cells by of apoptosis and in was using the and was and of a with are as by of by using for with a of A of was but Cell in an programmed cell an loss of cellular volume or apoptotic volume decrease is This is by the loss of intracellular sodium and but the role of anions and in chloride ions during is less (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 9Barbiero G. Duranti F. Bonelli G. Amenta J.S. Baccino F.M. Exp. Cell Res. 1995; 217: 410-418Crossref PubMed Scopus (141) Google Scholar). we changes in intracellular chloride concentration during or UV-C-induced apoptosis in Jurkat T-cells. with the to intracellular chloride This has been to intracellular chloride changes in cell J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. M. J. S. G. A. J. M. J. Physiol. PubMed Scopus Google Scholar, Br. J. PubMed Scopus Google Scholar), but not in apoptotic the is to the which is in the in a significant J. PubMed Scopus Google Scholar). is by by the of Jurkat with size in from to chloride A was the in a is the of chloride to in the of the chloride from the of the to the intracellular chloride concentration from of cells in the intracellular chloride we Jurkat in medium a concentration shown to inhibit chloride J. Biol. 1994; PubMed Scopus Google Scholar), or medium with reduced chloride to intracellular chloride J. Biol. 1994; PubMed Scopus Google Scholar, S. M. A. Res. 1997; PubMed Scopus Google Scholar, A. J. Physiol. 275: Scopus Google Scholar, F. PubMed Scopus Google Scholar). to the intracellular chloride concentration intracellular chloride concentration of Jurkat in was This is in with a reported for intracellular chloride in G. 1997; PubMed Scopus Google Scholar). of the chloride channel inhibitor SITS in an of intracellular chloride of In cells in a significant decrease in intracellular chloride to a to we intracellular chloride changes of apoptosis with either or UV-C a well studied of the apoptotic pathway. these Jurkat in medium or Apoptosis was either by the of or treatment with UV-C is of cells was of apoptosis by using a in the of cells to the was was with the to the intracellular chloride in apoptotic UV-C and not treatment in a significant decrease in intracellular chloride of loss in intracellular chloride is by of the cells with SITS Furthermore, chloride decrease in cells with UV-C that of their intracellular chloride to the in a medium with reduced chloride In was observed in the intracellular chloride of cells with in the of SITS or following intracellular chloride that but not apoptosis in Jurkat results in an intracellular chloride decrease that can be abolished by chloride flux the of UV-C-induced by is a characteristic of apoptotic cell and is to a loss of intracellular potassium (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar). was important to chloride flux modulation the of intracellular Jurkat and with either or UV-C to apoptosis as Cell size and intracellular potassium by using a with the treatment with or UV-C in medium in an increased of cells with reduced intracellular potassium and a cell size treatment with in the of SITS potassium by cell shrinkage In UV-C in the of SITS reduced cell shrinkage and the loss of potassium treatment in medium with reduced chloride not the of cells that and potassium In UV-C treatment of cells in medium with reduced chloride concentration the of cells apoptotic volume decrease and potassium loss a and the of cells in a for cells with intracellular potassium and cell size is in Clearly, and UV-C treatment results in an increased of cells potassium and cell In the of either the chloride channel inhibitor or the medium reduced the of cells with a cell size and a loss of In treatment with in the of SITS potassium and cell these that modulation of chloride flux by using either a chloride channel inhibitor or intracellular chloride the UV-C-induced loss of potassium and the of cells in Jurkat T-cells. the in during has been shown that of apoptosis is with changes in intracellular sodium (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, C.D. Cidlowski J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, we to chloride flux modulation changes in intracellular sodium in response to of apoptosis. with SITS or the to chloride reduced Jurkat either or UV-C are for the treatment with either or UV-C in a of cells with increased intracellular sodium the of the in medium In the of the chloride channel inhibitor both apoptotic in a cell for the intracellular which is observed for cells with we not an in sodium following either intracellular chloride by using medium with reduced chloride in a cell for the intracellular sodium with Furthermore, chloride the in intracellular sodium as with medium of cells in the for increased intracellular sodium the of the is in a with both in an increased of cells with increased intracellular both the chloride channel inhibitor and the medium the in intracellular sodium following both that chloride flux modulation is to the intracellular sodium and the apoptotic in intracellular sodium following both and apoptosis. the of UV-C-induced the of and the during apoptosis has been (2Bortner C.D. Gomez-Angelats M. Cidlowski J.A. J. Biol. Chem. 2001; 276: 4304-4314Abstract Full Text Full Text PDF PubMed Scopus (154) Google we the of following chloride flux Jurkat was by using F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google following the with SITS or the to medium to apoptosis cells a F. Ritter M. Gamper N. Huber S. Fillon S. Tanneur V. Lepple-Wienhues A. Szabo I. Gulbins E. Cell. Physiol. Biochem. 2000; 10: 417-428Crossref PubMed Scopus (211) Google for cells with cell In the of SITS or intracellular chloride a but decrease in the of cells with a was observed with either or UV-C both in cellular the chloride channel inhibitor chloride the response to In both chloride in the of UV-C treatment a distinct role of chloride in the intrinsic apoptotic pathway. is important to that with SITS and to medium in an increased of Thus, the of chloride flux the UV-C pathway is an Clearly, ion and are by the intrinsic and extrinsic apoptotic but apoptosis by the signaling pathway Bortner C.D. Cidlowski J.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Jurkat cells are which the as an signal for apoptosis. flux modulation affected ion and following UV-C but not typical early of apoptotic to and the signaling cascade is affected. Thus, we the of from the of the is affected by chloride flux of is a in the activation of the signaling pathway in the activation of Jurkat either in medium or medium with reduced chloride or with SITS to of apoptosis with either or of in the was by using a for Jurkat which the as a signal both in a significant of the with the A and with SITS the medium the of In of the cells with the chloride channel inhibitor the of following UV-C to a the the cells in medium to UV-C the of that the modulation of chloride flux upstream or the of to the of UV-C-induced UV-C-induced of a activation was by modulation of chloride was of to the downstream activation of caspases was affected. Apoptosis was by either the of or to UV-C and the of and of its was by with SITS or chloride both the of with UV-C but not chloride channel inhibitor of the following UV-C Furthermore, the of following UV-C is reduced in the of SITS or in chloride reduced medium from cells a of of modulation of chloride flux Thus, the chloride channel inhibitor SITS intracellular chloride the of activation or In both SITS and chloride to UV-C the of and its intracellular UV-C-induced of is a morphological feature of apoptosis. we the of chloride flux modulation during apoptosis. Jurkat of apoptosis with either or UV-C by with the chloride channel inhibitor SITS the medium with reduced chloride affected the and cell and with in a of cell and apoptotic in the or of SITS as well as In the of SITS in an of cells UV-C treatment in medium in the of cell and apoptotic with SITS as well as cell shrinkage and apoptotic medium the of UV-C Thus, the morphological changes typical for apoptosis by UV-C but not are by chloride flux UV-C-induced characteristic of apoptosis is the of the the of chloride flux modulation the and of the was of apoptosis with or UV-C the was either by or by of and cells with the of of cells with a reduced of and a a characteristic of apoptosis UV-C the characteristics of reduced and apoptotic In in with either the chloride channel inhibitor SITS or in medium UV-C was of cells with was by with or UV-C increased the of cells with with the with the chloride channel inhibitor SITS not by whereas SITS treatment to UV-C medium the of cells following In UV-C treatment in medium with reduced chloride that the following to UV-C but not treatment is reduced by modulation of chloride flux using either a chloride channel inhibitor or intracellular chloride the UV-C-induced to that chloride flux modulation affected but not apoptotic characteristics the of sodium in Jurkat which are cells the of as an signal for extrinsic cell the of this was not affected by chloride to upstream of the the UV-C-induced signaling cascade is affected. is well that are in response to we the of the kinase and kinase Apoptosis was by either the of or to UV-C and the of and and by UV-C but not and are with the chloride channel inhibitor SITS and intracellular chloride both reduced the of these In of chloride modulation in with Thus, chloride flux specifically the UV-C-induced kinase signaling cascade upstream of the that results in the of from the the This report for the that but not apoptosis in Jurkat is by a significant decrease in intracellular Furthermore, of chloride flux by of the chloride channel inhibitor SITS or intracellular chloride via of medium with reduced chloride J. Biol. 1994; PubMed Scopus Google Scholar, S. M. A. Res. 1997; PubMed Scopus Google Scholar, A. J. Physiol. 275: Scopus Google Scholar, F. PubMed Scopus Google but not apoptotic characteristics in Jurkat T-cells. Moreover, the activation of the kinase and following UV-C was abolished by chloride flux modulation, a role of chloride flux in the regulation of signaling that during apoptosis following of the intrinsic pathway the extrinsic pathway Cidlowski J.A. Exp. Cell Res. PubMed Scopus Google Scholar). In the we early and to ensure the apoptotic are and not Bortner C.D. Cidlowski J.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). a role for an alteration of the intracellular chloride concentration the activation of the apoptotic signaling pathway upstream of the to changes in intracellular which are to be in the regulation of and activation Jr., F.M. Cidlowski J.A. PubMed Scopus Google Scholar), changes in intracellular chloride to be crucial for the activation of signaling the of this is the report that the for of intracellular chloride changes during apoptosis by This was to intracellular chloride changes in cell by or J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. M. J. S. G. A. J. M. J. Physiol. PubMed Scopus Google Scholar, Br. J. PubMed Scopus Google has not been to changes during apoptosis. that of apoptosis with UV-C results in a significant decrease in intracellular is to that not the chloride decrease but chloride to be crucial for activation of the apoptotic signaling This can be from the that either using the chloride channel inhibitor SITS or intracellular chloride both UV-C-induced apoptosis. was that a decrease in intracellular chloride the loss of potassium that E. J. S. J. Physiol. 2001; Scopus Google Scholar, M. Cidlowski J.A. PubMed Scopus Google Scholar). Here we that the decrease in intracellular chloride during apoptosis of Jurkat cells is not a feature of apoptosis but the apoptotic using UV-C as a for the death pathway is in with the involvement of chloride ions in the regulation of apoptosis in of the that the chloride channel inhibitor apoptosis in cells and A. I. Cell Biol. Int. PubMed Scopus Google Scholar). Furthermore, chloride channel and been reported to cell morphological and in and cells apoptosis E. A. S. A. 2000; PubMed Scopus Google Scholar). a role for chloride ions in the signaling cascade the or upstream of the mitochondria, the to has not been In apoptosis in cells was by the of the chloride channel and a in chloride channel activity but not potassium A. S. M. Cell PubMed Scopus Google Scholar). in to potassium or sodium channel the chloride channel SITS was to decrease cellular and morphological changes as well as cell death in J. 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PubMed Scopus Google Scholar), that intrinsic activation of programmed cell death lead to the activation of outwardly rectifying chloride in this the role of volume-sensitive outwardly rectifying chloride in the activation and cell death was not outwardly rectifying chloride chloride with decrease in intracellular chloride is important to that the modulation of chloride ions not the of apoptosis but the intracellular concentration of sodium and ions are to an important role during volume the activation of the apoptotic signaling and apoptotic volume decrease. distinct for sodium and potassium C.D. Cidlowski J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was shown that whereas the loss of potassium is for the activation of caspases and nucleases Jr., F.M. Cidlowski J.A. PubMed Scopus Google Scholar), the sodium ions a crucial role in the regulation of the cellular volume of apoptotic events C.D. Cidlowski J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the a cell for the intracellular sodium was observed in and apoptotic following modulation of Furthermore, the in sodium intrinsic or extrinsic apoptosis was not observed the chloride channel inhibitor was or intracellular chloride was In was abolished by chloride flux modulation during but not apoptotic a in intracellular sodium not for these to chloride and their role in apoptosis H.H. Roe M.W. Fiekers J.F. Moore A.L. Lidofsky S.D. J. Biol. Chem. 2000; 275: 20556-20561Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, S. A. PubMed Scopus Google Scholar, I. Lepple-Wienhues A. M. Gulbins E. F. S. A. PubMed Scopus Google Scholar, E. A. S. A. 2000; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, A. S. M. Cell PubMed Scopus Google Scholar, A. I. Cell Biol. Int. PubMed Scopus Google Scholar). the SITS to chloride is that this of can and a report that the of apoptosis in is of the of S. N. 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