A role for the peroxisome proliferator-activated receptor alpha in T-cell physiology and ageing immunobiology

摘要

Peroxisome proliferator-activated receptor (PPAR) alpha represents an important member of the nuclear hormone receptor superfamily that can be activated by a variety of natural fatty acids, some of their metabolites and by commonly-used anti-lipidaemic drugs. We recently demonstrated PPARalpha expression in T lymphocytes, where it controls the initiation of transcription of T-box expressed in T-cells (T-bet) independent of added agonist. T-bet is an activation-inducible transcription factor regulator of interleukin 2 (suppression) and interferon gamma (stimulation) synthesis. A suppressed ability to produce interleukin 2 and an enhanced production of interferon gamma occurs in activated T-cells from PPARalpha-/- mice, as well as in T-cells from wildtype aged animals whose lymphocytes express lowered basal levels of PPARalpha. The dysregulated expression and/or function of cytokines, glucocorticoids or leptin that occurs with advanced age could all be responsible for the reduced expression of PPARalpha. Dietary supplementation of aged mice with vitamin E, or supplementation with known agonists of PPARalpha, was associated with elevation of lymphocyte expression of this nuclear hormone receptor, restoration of control over T-bet expression and elimination of the dysregulated production of interleukin 2 and interferon gamma following lymphocyte activation. Interleukin 2 and interferon gamma play very important roles in the initiation and/or regulation of immune, inflammatory and autoimmune disease states. Thus, the mechanisms that control the timing, magnitude and duration of specific cytokine production by activated T lymphocytes need clarification before appropriate nutritional or therapeutic strategies can be devised to treat disease conditions where cytokine expression and/or activities are deemed to be dysregulated and responsible.