Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

详细信息    查看全文

• 作者：Masato Ogura^a ; Haruhisa Kikuchi^b ; Toshiyuki Suzuki^a ; Junko Yamaki^a ; Miwako K. Homma^a ; Yoshiteru Oshima^b ; Yoshimi Homma^a ; ^{yoshihom@fmu.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cytokine ; Immune response ; Immunosuppressant ; Dermatitis ; Small molecule
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 April 2016
• 年：2016
• 卷：105
• 期：Complete
• 页码：55-65
• 全文大小：3748 K

文摘

Development of new immunosuppressing agents is necessary in organ transplantation or immune diseases. Because Ppc-1 exhibits a suppressing effect on interleukin-2 (IL2) production in Jurkat cells, we synthesized and screened Ppc-1 derivatives that preserve prenylated quinolinecarboxylic acid (PQA) structure, and identified compound 18 (PQA-18) as a novel molecule with immunosuppressing effect. PQA-18 suppressed not only IL2 but also IL4, IL6, and tumor necrosis factor-α production in human peripheral lymphocytes without affecting cell viability. Two-dimensional gel electrophoresis analysis and in vitro kinase assay revealed that PQA-18 inhibits kinase activity of p21-activated kinase 2 (PAK2). Administration of PQA-18 by intraperitoneal injection suppressed the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens in mice. Treatment with the PQA-18 ointment on Nc/Nga mice, a model of human atopic dermatitis, improved skin lesions and serum IgE levels. These results suggest that PQA-18 is a unique PAK2 inhibitor with potent immunosuppressing effects in vitro and in vivo. PQA-18 may be a valuable lead for the development of novel immunosuppressants.