Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

Masato Ogura, Haruhisa Kikuchi, Toshiyuki Suzuki, Junko Yamaki, Miwako K. Homma, Yoshiteru Oshima, Yoshimi Homma

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalBiochemical Pharmacology
Volume105
DOIs
Publication statusPublished - 2016 Apr 1
Externally publishedYes

Keywords

  • Cytokine
  • Dermatitis
  • Immune response
  • Immunosuppressant
  • Small molecule

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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