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Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity.

Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN - J. Exp. Med. (2004)

Bottom Line: Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential.Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax.Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

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Related in: MedlinePlus

Participation of the intrinsic pathway of apoptosis in p21āˆ’/āˆ’ T cells from male BXSB mice. Increased p53 and reduced Bcl-2 expression in activated p21āˆ’/āˆ’ T cells. T cells (n = 5 mice/group) were activated with 10 Ī¼g/ml anti-CD3 plus 5 Ī¼g/ml anti-CD28, and lysates were analyzed by Western blot.
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fig5: Participation of the intrinsic pathway of apoptosis in p21āˆ’/āˆ’ T cells from male BXSB mice. Increased p53 and reduced Bcl-2 expression in activated p21āˆ’/āˆ’ T cells. T cells (n = 5 mice/group) were activated with 10 Ī¼g/ml anti-CD3 plus 5 Ī¼g/ml anti-CD28, and lysates were analyzed by Western blot.

Mentions: Although the extrinsic CD95-mediated apoptosis pathway is generally sufficient for AICD, depending on cell type and/or signal strength, the intrinsic pathway may facilitate this process (38ā€“40). p21āˆ’/āˆ’ T cells cultured with anti-CD3 and anti-CD28 for 48 h expressed 1.9-fold more p53 and 1.7-fold less Bcl-2 protein than control cells. Although Bax expression was unaltered, the ratio of Bax/Bcl-2 shifted moderately toward the proapoptotic Bax (5.3 in p21āˆ’/āˆ’ vs. 3.1 in p21+/+) (Fig. 5; P < 0.05). In addition, activated wild-type T cells cultured in the presence of transfecting p21 AS oligonucleotides showed a 1.7-fold decrease in Bcl-2 and, in this case, a 1.9-fold increase in Bax expression, resulting in a more pronounced shift in the Bax/Bcl-2 ratio (8.1; P < 0.05).


Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity.

Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN - J. Exp. Med. (2004)

Participation of the intrinsic pathway of apoptosis in p21āˆ’/āˆ’ T cells from male BXSB mice. Increased p53 and reduced Bcl-2 expression in activated p21āˆ’/āˆ’ T cells. T cells (n = 5 mice/group) were activated with 10 Ī¼g/ml anti-CD3 plus 5 Ī¼g/ml anti-CD28, and lysates were analyzed by Western blot.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211831&req=5

fig5: Participation of the intrinsic pathway of apoptosis in p21āˆ’/āˆ’ T cells from male BXSB mice. Increased p53 and reduced Bcl-2 expression in activated p21āˆ’/āˆ’ T cells. T cells (n = 5 mice/group) were activated with 10 Ī¼g/ml anti-CD3 plus 5 Ī¼g/ml anti-CD28, and lysates were analyzed by Western blot.
Mentions: Although the extrinsic CD95-mediated apoptosis pathway is generally sufficient for AICD, depending on cell type and/or signal strength, the intrinsic pathway may facilitate this process (38ā€“40). p21āˆ’/āˆ’ T cells cultured with anti-CD3 and anti-CD28 for 48 h expressed 1.9-fold more p53 and 1.7-fold less Bcl-2 protein than control cells. Although Bax expression was unaltered, the ratio of Bax/Bcl-2 shifted moderately toward the proapoptotic Bax (5.3 in p21āˆ’/āˆ’ vs. 3.1 in p21+/+) (Fig. 5; P < 0.05). In addition, activated wild-type T cells cultured in the presence of transfecting p21 AS oligonucleotides showed a 1.7-fold decrease in Bcl-2 and, in this case, a 1.9-fold increase in Bax expression, resulting in a more pronounced shift in the Bax/Bcl-2 ratio (8.1; P < 0.05).

Bottom Line: Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential.Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax.Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

Show MeSH
Related in: MedlinePlus