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* Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, Turku, Finland;
Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland;
Department of Biology, Åbo Akademi University, Turku, Finland, and
Department of Biology, University of Turku, Turku, Finland
Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIPS) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIPS, the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIPS. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was financed by the Academy of Finland, TEKES, the Finnish Life Insurance Companies, the Sigrid Jusélius Foundation, the Finnish Cancer Organizations, and Åbo Akademi University. A.M., T.S.S., A.K., and M.P. were supported by Turku Graduate School of Biomedical Sciences.
2 Current address: European Molecular Biology Laboratory, Developmental Biology Unit, D-69117 Heidelberg, Germany.
3 Address correspondence and reprint requests to Prof. John E. Eriksson, Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, FI-20521 Turku, Finland. E-mail address: john.eriksson{at}abo.fi
4 Abbreviations used in this paper: Hsp, heat shock protein; c-FLIP, cellular FLICE-inhibitory protein; c-FLIPS, c-FLIPshort; c-FLIPL, c-FLIPlong; DISC, death-inducing signaling complex; CHX, cycloheximide; HS, heat shock treatment.
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  M. R. Abedini, E. J. Muller, J. Brun, R. Bergeron, D. A. Gray, and B. K. Tsang Cisplatin Induces p53-Dependent FLICE-Like Inhibitory Protein Ubiquitination in Ovarian Cancer Cells Cancer Res., June 15, 2008; 68(12): 4511 - 4517. [Abstract] [Full Text] [PDF]
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