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Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.

Bohgaki T, Mozo J, Salmena L, Matysiak-Zablocki E, Bohgaki M, Sanchez O, Strasser A, Hakem A, Hakem R - J. Cell Biol. (2011)

Bottom Line: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer.In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis.We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.

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Loss of caspase-8 in T cells suppresses the hypergammaglobulinemia caused by loss of Bim. (A) Levels of IgM, IgG1, IgG2a, IgG2b, and IgG3 in sera of 6 mo or older WT, Bim−/−, tcasp8−/−, and tcasp8−/−Bim−/− mice (n = 18–30). (B) Levels of ANA in sera of 6 mo or older tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT mice. Solid horizontal lines represent the mean for each genotype. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice.
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fig6: Loss of caspase-8 in T cells suppresses the hypergammaglobulinemia caused by loss of Bim. (A) Levels of IgM, IgG1, IgG2a, IgG2b, and IgG3 in sera of 6 mo or older WT, Bim−/−, tcasp8−/−, and tcasp8−/−Bim−/− mice (n = 18–30). (B) Levels of ANA in sera of 6 mo or older tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT mice. Solid horizontal lines represent the mean for each genotype. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice.

Mentions: To determine the effect of combined loss of both caspase-8 and Bim on the immunopathology associated with their individual inactivation, the levels of immunoglobulins, and ANA in sera from the old mice were examined using ELISA. In contrast to old Bim−/− mice, age-matched tcasp8−/−Bim−/− littermates exhibited significantly decreased serum levels of ANA, and their overall levels of IgM, IgG1, IgG2a, and IgG3 were also reduced to the levels found in WT littermates (Figs. 6, A and B).


Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.

Bohgaki T, Mozo J, Salmena L, Matysiak-Zablocki E, Bohgaki M, Sanchez O, Strasser A, Hakem A, Hakem R - J. Cell Biol. (2011)

Loss of caspase-8 in T cells suppresses the hypergammaglobulinemia caused by loss of Bim. (A) Levels of IgM, IgG1, IgG2a, IgG2b, and IgG3 in sera of 6 mo or older WT, Bim−/−, tcasp8−/−, and tcasp8−/−Bim−/− mice (n = 18–30). (B) Levels of ANA in sera of 6 mo or older tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT mice. Solid horizontal lines represent the mean for each genotype. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3198166&req=5

fig6: Loss of caspase-8 in T cells suppresses the hypergammaglobulinemia caused by loss of Bim. (A) Levels of IgM, IgG1, IgG2a, IgG2b, and IgG3 in sera of 6 mo or older WT, Bim−/−, tcasp8−/−, and tcasp8−/−Bim−/− mice (n = 18–30). (B) Levels of ANA in sera of 6 mo or older tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT mice. Solid horizontal lines represent the mean for each genotype. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice.
Mentions: To determine the effect of combined loss of both caspase-8 and Bim on the immunopathology associated with their individual inactivation, the levels of immunoglobulins, and ANA in sera from the old mice were examined using ELISA. In contrast to old Bim−/− mice, age-matched tcasp8−/−Bim−/− littermates exhibited significantly decreased serum levels of ANA, and their overall levels of IgM, IgG1, IgG2a, and IgG3 were also reduced to the levels found in WT littermates (Figs. 6, A and B).

Bottom Line: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer.In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis.We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.

Show MeSH
Related in: MedlinePlus