Limits...
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.

Show MeSH

Related in: MedlinePlus

Decreased autoimmune disease in male p21−/− BXSB mice. (a and b) Reduced serum polyclonal (left) and antichromatin (right) IgG subclasses in 4-mo-old male BXSB p21−/− mice (n = 8 mice/group; mean ± SEM). (shaded bars) BXSB p21−/− mice. (unshaded bars) p21+/+ BXSB mice. For all polyclonal and antichromatin total and subclass IgG levels, P < 0.05 for p21−/− versus p21+/+. (c) Increased cumulative survival rates of p21−/− BXSB mice (P < 0.0001). Male BXSB p21+/+ (n = 16) and p21−/− (n = 15) littermates were followed for up to 500 d. (•) BXSB p21−/− mice. (○) BXSB p21+/+ mice. (d) Glomerular pathology (top) and IgG deposits (bottom) of representative 4-mo-old p21+/+ and p21−/− mice. Increased segmental mesangial proliferation and accumulation of periodic-acid Schiff–positive mesangial matrix material were seen in p21+/+ mice, whereas p21−/− mice exhibited significantly less glomerular damage, as well as decreased segmental granular mesangial and capillary wall deposits of IgG (top, 630×; bottom, 400×).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211831&req=5

fig1: Decreased autoimmune disease in male p21−/− BXSB mice. (a and b) Reduced serum polyclonal (left) and antichromatin (right) IgG subclasses in 4-mo-old male BXSB p21−/− mice (n = 8 mice/group; mean ± SEM). (shaded bars) BXSB p21−/− mice. (unshaded bars) p21+/+ BXSB mice. For all polyclonal and antichromatin total and subclass IgG levels, P < 0.05 for p21−/− versus p21+/+. (c) Increased cumulative survival rates of p21−/− BXSB mice (P < 0.0001). Male BXSB p21+/+ (n = 16) and p21−/− (n = 15) littermates were followed for up to 500 d. (•) BXSB p21−/− mice. (○) BXSB p21+/+ mice. (d) Glomerular pathology (top) and IgG deposits (bottom) of representative 4-mo-old p21+/+ and p21−/− mice. Increased segmental mesangial proliferation and accumulation of periodic-acid Schiff–positive mesangial matrix material were seen in p21+/+ mice, whereas p21−/− mice exhibited significantly less glomerular damage, as well as decreased segmental granular mesangial and capillary wall deposits of IgG (top, 630×; bottom, 400×).

Mentions: Initial studies were performed to determine the effects of p21 deficiency on autoimmune manifestations. Control mice exhibited typical hypergammaglobulinemia at 4 mo of age, whereas all IgG subclasses were significantly lower in p21−/− littermates, approaching levels seen in C57BL/6 normal mice (Fig. 1 a). Antichromatin levels, predominantly of the IgG2a subclass, were also high in the wild-type littermates. In contrast, antichromatin autoantibodies of all subclasses were greatly reduced in the p21−/− mice (Fig. 1 b).


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)

Decreased autoimmune disease in male p21−/− BXSB mice. (a and b) Reduced serum polyclonal (left) and antichromatin (right) IgG subclasses in 4-mo-old male BXSB p21−/− mice (n = 8 mice/group; mean ± SEM). (shaded bars) BXSB p21−/− mice. (unshaded bars) p21+/+ BXSB mice. For all polyclonal and antichromatin total and subclass IgG levels, P < 0.05 for p21−/− versus p21+/+. (c) Increased cumulative survival rates of p21−/− BXSB mice (P < 0.0001). Male BXSB p21+/+ (n = 16) and p21−/− (n = 15) littermates were followed for up to 500 d. (•) BXSB p21−/− mice. (○) BXSB p21+/+ mice. (d) Glomerular pathology (top) and IgG deposits (bottom) of representative 4-mo-old p21+/+ and p21−/− mice. Increased segmental mesangial proliferation and accumulation of periodic-acid Schiff–positive mesangial matrix material were seen in p21+/+ mice, whereas p21−/− mice exhibited significantly less glomerular damage, as well as decreased segmental granular mesangial and capillary wall deposits of IgG (top, 630×; bottom, 400×).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Decreased autoimmune disease in male p21−/− BXSB mice. (a and b) Reduced serum polyclonal (left) and antichromatin (right) IgG subclasses in 4-mo-old male BXSB p21−/− mice (n = 8 mice/group; mean ± SEM). (shaded bars) BXSB p21−/− mice. (unshaded bars) p21+/+ BXSB mice. For all polyclonal and antichromatin total and subclass IgG levels, P < 0.05 for p21−/− versus p21+/+. (c) Increased cumulative survival rates of p21−/− BXSB mice (P < 0.0001). Male BXSB p21+/+ (n = 16) and p21−/− (n = 15) littermates were followed for up to 500 d. (•) BXSB p21−/− mice. (○) BXSB p21+/+ mice. (d) Glomerular pathology (top) and IgG deposits (bottom) of representative 4-mo-old p21+/+ and p21−/− mice. Increased segmental mesangial proliferation and accumulation of periodic-acid Schiff–positive mesangial matrix material were seen in p21+/+ mice, whereas p21−/− mice exhibited significantly less glomerular damage, as well as decreased segmental granular mesangial and capillary wall deposits of IgG (top, 630×; bottom, 400×).
Mentions: Initial studies were performed to determine the effects of p21 deficiency on autoimmune manifestations. Control mice exhibited typical hypergammaglobulinemia at 4 mo of age, whereas all IgG subclasses were significantly lower in p21−/− littermates, approaching levels seen in C57BL/6 normal mice (Fig. 1 a). Antichromatin levels, predominantly of the IgG2a subclass, were also high in the wild-type littermates. In contrast, antichromatin autoantibodies of all subclasses were greatly reduced in the p21−/− mice (Fig. 1 b).

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