Bidirectional immunoregulation of calcineurin inhibitor tacrolimus on FOXP3 transcription?

• Published in: Medical hypotheses 2011-02, Vol.76 (2), p.178-180
• Main Authors: Shen, Zhu, Song, Qiuhe, Chen, Ling, Zhong, Baiyu, Tang, Shuqian, Hao, Fei
• Format: Article
• Language: English
• Subjects: Animals; Calcineurin Inhibitors; Cell Nucleus - metabolism; Dose-Response Relationship, Drug; Forkhead Transcription Factors - metabolism; GATA3 Transcription Factor - metabolism; Gene Expression Regulation; Humans; Immunosuppressive Agents - pharmacology; Internal Medicine; NFATC Transcription Factors - metabolism; Psoriasis - metabolism; STAT6 Transcription Factor - metabolism; T-Lymphocytes, Regulatory - metabolism; Tacrolimus - pharmacology; Transcription Factors - metabolism
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2010.09.011

Summary The imbalance between regulatory T cells (Treg) and effector T cells is important for maintaining of psoriasis vulgaris. FOXP3 is a master control transcription factor for the development and function of Tregs and is critical for transcriptional repression. Tacrolimus is effective in treatment of psoriasis vulgaris. Data show that tacrolimus has multiple impacts on FOXP3, but the exact pharmacological mechanism of tacrolimus on FOXP3 have yet to be elucidated. We herein suggest the bidirectional immunoregulation of tacrolimus on FOXP3. High concentration of tacrolimus renders the cooperation of NFAT with STAT6 and NF-κB to activate GATA3 transcription. On the contrary, low concentration of tacrolimus results in higher nucleus level of NFAT, which directly binds to FOXP3 enhancer and/or cooperates with Smad3 to activate FOXP3 transcription. Further studies using loss of function and over-expression methods are needed to determine the detailed molecules involved in this bidirectional immunoregulation of tacrolimus on FOXP3.