Regulation of Death Receptor Responses by Hyperthermia
Meinander, Annika (2007-06-01)
Åbo Akademi - Åbo Akademi University
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Cells need a variety of responses to protect themselves against stresses caused by changes in the environment. Likewise, a complex apoptotic machinery is necessary for elimination of cells that are no longer needed in the organism or that have been terminally damaged. Hence, a carefully regulated balance between protecting and destructive signals is required. As Tlymphocytes are determinants of host defenses during infections, strict regulation of Tlymphocyte homeostasis is a prerequisite for a functional immune response. The Tlymphocyte population dramatically expands upon inflammatory responses and the excess cells need to be deleted to regain homeostasis after antigen clearance. The elimination of excess T-lymphocytes from the organism is conducted by activation-induced cell death, which involves death receptor signaling via CD95. The sensitivity to apoptosis mediated via CD95 is, therefore, a key determinant of T-lymphocyte persistence. Elevation of the body temperature during fever has been proposed to have a major impact on immune responses during infections. Fever influences the clonal expansion and proliferation of T-lymphocytes, and it may thereby modulate the survival and endurance of T-lymphocyte populations. In this study, we show that fever-like hyperthermia sensitizes activated human T-lymphocytes to CD95-mediated apoptosis. Interestingly, many of the proteins induced and/or activated during hyperthermia, such as the stress-induced MAP kinases and the molecular chaperone Hsp70, are not responsible for the hyperthermia-induced sensitization to CD95-mediated apoptosis, indicating that hyperthermia directly affects one or more components of the CD95-mediated apoptotic cascade. A modulator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated. Hyperthermia triggers downregulation of both c-FLIP splicing variants, c-FLIPS and c-FLIPL, with consequent sensitization to apoptosis mediated via CD95. Furthermore, c-FLIP downregulation and the subsequent sensitization are specific for hyperthermic stress. Finally, we demonstrate that the hyperthermia-mediated downregulation of c-FLIP as well as the sensitization to CD95-mediated apoptosis are due to increased ubiquitination and proteasomal degradation of c-FLIPS. High quantities of c-FLIP and impaired lymphocyte apoptosis are associated with several autoimmune diseases. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through c-FLIPS depletion, which might be beneficial for elimination of autoreactive lymphocytes otherwise able to induce autoimmune diseases or allergy. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for the fever-mediated regulation of immune responses.