title: Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2.
abstract: 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.
authors.affiliation: Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8678, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaki
authors.affiliation: Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Miwako K
authors.initials: MK
authors.lastname: Homma
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8678, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. Electronic address: yoshihom@fmu.ac.jp.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Homma
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D003872:Dermatitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054876:Prenylation / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014283:Triiodobenzoic Acids / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D007166:Immunosuppressive Agents; D011804:Quinolines; D014283:Triiodobenzoic Acids; C012625:compound 18; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases
keywords: Cytokine; Dermatitis; Immune response; Immunosuppressant; PQA-18 (PubChem CID: 73602831); Ppc-1 (PubChem CID: 46910769); Small molecule