Participation of FLIP, RIP and Bcl-x(L) in fas-mediated T-cell death

• Apart from the conventional Fas signalling pathway, alternative pathways including the mitochondrial caspase-dependent and RIP-mediated cell death routes have been proposed to operate during Fas-mediated cell death. To evaluate the contribution of different Fas signalling pathways, mice overexpressing FLIPL, Bcl-x(L), a kinase-deficient form of RIP (RIP Delta kin) or combinations thereof were generated by retroviral gene transfer of haematopoietic stem cells. Such mice did not show overt abnormalities in haematopoietic development, defects in thymic deletion, accumulation of double-negative T cells or signs of autoimmunity. Fas-mediated death of mitogen-activated T cells was caspase dependent and could be blocked by FLIPL overexpression only with the minor involvement of Bcl-x(L) or RIP Delta kin inhibitable pathways. Fas-mediated death of resting CD4(+) and CD8(+) T cells was mainly caspase dependent but could only partly be blocked by FLIPL overexpression. Both Bcl-x(L) or RIP Delta kin expression resulted in partial protection of CD8(+) T cells against Fas-mediated cell death. These results indicate that yet uncharacterized signalling pathways from the Fas receptor are critically involved in lymphoproliferative and autoimmune disease observed in lpr mice and autoimmune lymphoproliferative syndrome patients.

Ämnesord

NATURVETENSKAP  -- Biologi -- Immunologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Immunology (hsv//eng)

Nyckelord

tumor-necrosis-factor

interacting protein

adapter molecule

deficient mice

c-flip

apoptosis

activation

bcl-2

expression

pathway

Immunology

Immunologi

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)