In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice

Article

关键词: TUMOR-NECROSIS-FACTOR;    PHOSPHODIESTERASE INHIBITOR;    FACTOR-ALPHA;    TNF-ALPHA;    PENTOXIFYLLINE;    ATHEROSCLEROSIS;    ENCEPHALOMYELITIS;    INTERLEUKIN-12;    LISOFYLLINE;    PREVENTION;   

DOI  :  10.1161/01.CIR.104.2.197

来源: SCIE

【 摘 要 】

Background-A chronic immune response involving proinflammatory T helper cell 1 (Th1) lymphocyte activation occurs in the atherosclerotic lesion, but whether this activation is protective or deleterious remains unclear. Methods and Results-We modulated the immune response of the atherosclerosis-prone apolipoprotein E-deficient (apoE(-/-)) mouse. Eight-week-old apoE-/- mice were treated daily with pentosifylline (PTX), a known inhibitor of the Th1 differentiation pathway, or PBS (control) for 4 weeks or 12 weeks. Twelve-week PTX treatment reduced atherosclerotic lesion size by 60% (P <0.01). PTX-treated mice developed lesions that were limited to the degree of fatty streaks. In contrast, control mice developed mature fibrofatty atherosclerotic lesions. In parallel, the proportion of interferon (IFN)-gamma -producing Th1 splenic lymphocytes was significantly reduced by PTX, and lesion size was correlated to the proportion of IFN-gamma (+) T cells. In vitro addition of PTX to cultured spleen cells did not modify the production of IFN-gamma but increased the production of IL-10 by T cells, indicating that PTX does not suppress IFN-gamma production but rather blocks Th1 polarization while promoting Th2 polarization. Conclusions-Thus, PTX protected mice from atherosclerosis by reducing the Th1 polarization of T helper lymphocytes. This study demonstrates that the Th1 immune response associated with atherosclerosis is deleterious and that a modulation of the Th1 differentiation pathway may provide a new pharmacological tool to treat this disease.

【 授权许可】

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