Expression of Fas-associated death domain-like interleukin-1?-converting enzyme (FLICE) inhibitory protein (FLIP) in human articular chondrocytes: possible contribution to the resistance to Fas-mediated death of in vitro cultured human articular chondrocytes

Activation-induced cell death (AICD) plays an important role in peripheral T-cell tolerance. AICD in CD4 T helper (Th) cells, including Th1 and Th2 effectors, has been extensively studied. Recently, interleukin-17–producing CD4+ T cells (Th17 cells) have been identified as a unique Th subset, but their susceptibility to AICD and the underlying molecular mechanisms have not been defined. In this study, we found that Th17 cells were significantly less susceptible to AICD than Th1 cells, and Th17 cell resistance to AICD is due to the high levels of c-Fas–associated death domain–like interleukin-1–converting enzyme inhibitory protein preventing Fas-mediated apoptosis. The resistance of Th17 cells to AICD reveals a novel mechanism to explain the high pathogenicity of Th17 cells in autoimmune diseases, and may also provide a rationale to generate tumor-specific Th17 cells for adoptive immunotherapy.

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Critical Role for Fas-Associated Death Domain-Like Interleukin-1-Converting Enzyme-Like Inhibitory Protein in Anoikis Resistance and Distant Tumor Formation

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djk182 ◽

2007 ◽

Vol 99 (10) ◽

pp. 811-822 ◽

Cited By ~ 50

Author(s):

I. A. Mawji ◽

C. D. Simpson ◽

R. Hurren ◽

M. Gronda ◽

M. A. Williams ◽

...

Keyword(s):

Interleukin 1 ◽

Critical Role ◽

Tumor Formation ◽

Death Domain ◽

Converting Enzyme ◽

Anoikis Resistance ◽

Inhibitory Protein ◽

Distant Tumor

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Cultured Murine Thyroid Epithelial Cells Expressing Transgenic Fas-Associated Death Domain-Like Interleukin-1β Converting Enzyme Inhibitory Protein Are Protected from Fas-Mediated Apoptosis

Endocrinology ◽

10.1210/en.2008-0080 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3321-3329 ◽

Cited By ~ 18

Author(s):

Yujiang Fang ◽

Helen Braley-Mullen

Keyword(s):

Epithelial Cells ◽

Autoimmune Thyroiditis ◽

Death Domain ◽

Converting Enzyme ◽

Experimental Autoimmune Thyroiditis ◽

Inhibitory Protein ◽

Rna Transfection ◽

Experimental Autoimmune

The antiapoptotic molecule Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (FLIP) inhibits Fas-mediated apoptosis by blocking activation of caspase-8. We previously showed that expression of transgenic FLIP on thyroid epithelial cells (TECs) of DBA/1 and CBA/J mice promoted earlier resolution of granulomatous experimental autoimmune thyroiditis in vivo. This study was undertaken to directly determine whether transgenic FLIP expressed on cultured TECs can protect TECs from Fas-mediated apoptosis in vitro. The results indicate that cultured TECs from DBA/1 and CBA/J mice can be sensitized in vitro by interferon-γ and TNF-α to undergo Fas-mediated apoptosis. Transgenic overexpression of FLIP protected cultured TECs of FLIP transgene (Tg)+ DBA/1 and CBA/J mice from Fas-mediated apoptosis, and FLIP small interfering RNA transfection of cultured TECs of FLIP Tg+ DBA/1 and CBA/J mice abolished the protective effect. These in vitro results are consistent with our previous in vivo studies using DBA/1 and CBA/J FLIP Tg+ mice and provide direct support for the hypothesis that transgenic expression of FLIP promotes resolution of granulomatous experimental autoimmune thyroiditis by protecting TECs from apoptosis.

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