regulatory T cells (Tregs) play a critical role in maintaining immune self-tolerance. Reduced number and activity of Tregs are usually found in autoimmune and inflammatory diseases, and enhancing the differentiation of Tregs may be a promising therapeutic strategy. Some reports suggested an anti-inflammatory and anti-autoimmune potential for fenofibrate, a hypolipidemic drug used worldwide, whose lipid effects are mediated by the activation of peroxisome proliferator-activated receptor (PPAR ). In the present paper, we found that fenofibrate dose-dependently increased transforming growth factor- and interleukin-2-induced Treg differentiation in vitro, by 1.96-fold from 0 to 20？ M ( % to %, ). Other PPAR activators, WY14643 (100？ M), gemfibrozil (50？ M), and bezafibrate (30？ M), could not enhance Treg differentiation. In addition, PPAR could not upregulate the promoter activity of the Treg-specific transcription factor Foxp3. Fenofibrate might exert its function by enhancing Smad3 phosphorylation, a critical signal in Treg differentiation, via Akt suppression. Our work reveals a new PPAR independent anti-inflammatory mechanism of fenofibrate in up-regulating mouse Treg differentiation. 1. Introduction The immune function is normally delicately regulated to maintain both host defense and self-tolerance. Apart from negative selection in the process of T-cell development, recently discovered Foxp3+ regulatory T cells (Tregs) represent another important aspect in preventing self-immune reaction [1]. Tregs are a unique group of T cells that mainly suppress immune reaction and inflammation caused by other immune cells [1]. The dysfunction and reduction in number of Tregs are found in many autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, psoriasis [2], and atherosclerosis [3]. Enhancing the Treg amount may be a promising therapeutic target for these diseases. Atherosclerosis is widely known as a chronic inflammatory disease with the malfunction of multiple subsets of immune cells [4, 5]. We and others have revealed a reduced Treg number involved in deteriorated atherosclerosis [3, 6]. As a widely used lipid-lowering anti-atherosclerosis drug [7], fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) activator, has been intensely studied. PPARα-dependent and -independent anti-inflammatory activities were reported to play an important role in the function of fenofibrate, such as inhibiting NF-κB activity in inflammation-related cells [7,
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