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

doi:10.1016/j.bcp.2016.01.020

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

PHA - Molecular Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

11 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 language	English
Pages (from-to)	55-65
Number of pages	11
Journal	Biochemical Pharmacology
Volume	105
DOIs	https://doi.org/10.1016/j.bcp.2016.01.020
Publication status	Published - 2016 Apr 1

Keywords

Cytokine
Dermatitis
Immune response
Immunosuppressant
Small molecule

ASJC Scopus subject areas

Biochemistry
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bcp.2016.01.020

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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.",

keywords = "Cytokine, Dermatitis, Immune response, Immunosuppressant, Small molecule",

author = "Masato Ogura and Haruhisa Kikuchi and Toshiyuki Suzuki and Junko Yamaki and Homma, {Miwako K.} and Yoshiteru Oshima and Yoshimi Homma",

note = "Funding Information: This work was funded by the Japan Society for the Promotion of Science – Japan (Grant-in-Aid for Scientific Research), the Japan Science and Technology Agency – Japan (A-STEP), and Fukushima Medical University (grant for Project Research). The authors are indebted to Y. Naruse for technical assistance. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc. All rights reserved.",

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doi = "10.1016/j.bcp.2016.01.020",

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AU - Ogura, Masato

AU - Kikuchi, Haruhisa

AU - Suzuki, Toshiyuki

AU - Yamaki, Junko

AU - Homma, Miwako K.

AU - Oshima, Yoshiteru

AU - Homma, Yoshimi

N1 - Funding Information: This work was funded by the Japan Society for the Promotion of Science – Japan (Grant-in-Aid for Scientific Research), the Japan Science and Technology Agency – Japan (A-STEP), and Fukushima Medical University (grant for Project Research). The authors are indebted to Y. Naruse for technical assistance. Publisher Copyright: © 2016 Elsevier Inc. All rights reserved.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

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KW - Dermatitis

KW - Immune response

KW - Immunosuppressant

KW - Small molecule

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ER -

Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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