Dipeptidyl peptidase IV inhibitor analogs Cm Inhibit T cell Activation by Down-regulation AP – 1 and NF- κB signaling

• Main Authors: Chiang Meng-lin, 江孟霖
• Other Authors: Jenn Haung, Lai
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/92529733478580236416

碩士 === 國防醫學院 === 微生物及免疫學研究所 === 98 === Rheumatoid Arthritis(RA) is chronic inflammatory autoimmune disease. For the treatment of RA, Disease-modifying antirheumatic drugs (DMARDs) are frequently used. Inhibition T cell function is another approach to therapeutic target of RA. Dipeptidyl peptidase IV(DPP IV,CD26) is not only a serine protease that cleaves dipeptides from the N- -terminal polypeptide after a proline or an alanine, but also contain various cellular function such as co-stimulatory molecule for T cell, interaction with CD45, and adhesion molecule. In recent year, DPP IV inhibitor is used in diabetes mellitus patients. Here, we plan to investigate whether DPP IV inhibitor analogs can inhibit T cell activation and study its mechanisms. We used human peripheral blood T cells as a model system. We first screened 93 small molecules and examined its effect on activated T cells produced IL – 2 secretion by ELISA. Among then, we found Cm had the most potential suppression effect on T cell activation. . Further, Cm dose dependent ameliorate adhesion molecules(CD25/CD69/CD71) expression and other pro-inflammatory cytokines(IL-2/INF-γ/TNF-α) secretion by activated T cell. Cm potently inhibits IL-2( IC50 = 6.10 ± 0.08 M) ,INF-γ(IC50 = 6.10 ± 0.08 M) ,and TNF-α: (IC50= 8.08 ± 0.26) production on T cells. Subsequently, EMSA and western blot data shown Cm inhibit T cell activation through down-regulation AP – 1 and NF- κB signaling. However, Cm did not affect NFAT transcription factor binding. In the future, I plan to examine the in vivo effect of Cm in collagen induced arthritis animal model. Hopefully, this DPP IV inhibitor analog Cm can be another therapeutic choice for RA patients.