Anti-inflammatory and Immunomodulatory Properties of 2-Amino-3H-phenoxazin-3-one

Keizo Kohno; Masaki Miyake; Osamu Sano; Mari Tanaka-Kataoka; Shigeto Yamamoto; Satomi Koya-Miyata; Norie Arai; Mitsukiyo Fujii; Hikaru Watanabe; Shimpei Ushio; Kanso Iwaki; Shigeharu Fukuda

doi:10.1248/bpb.31.1938

Regular Articles

Anti-inflammatory and Immunomodulatory Properties of 2-Amino-3H-phenoxazin-3-one

Keizo Kohno, Masaki Miyake, Osamu Sano, Mari Tanaka-Kataoka, Shigeto Yamamoto, Satomi Koya-Miyata, Norie Arai, Mitsukiyo Fujii, Hikaru Watanabe, Shimpei Ushio, Kanso Iwaki, Shigeharu Fukuda

Author information

Keizo Kohno
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Masaki Miyake
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Osamu Sano
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Mari Tanaka-Kataoka
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Shigeto Yamamoto
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Satomi Koya-Miyata
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Norie Arai
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Mitsukiyo Fujii
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Hikaru Watanabe
Glycoscience Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Shimpei Ushio
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Kanso Iwaki
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.
Shigeharu Fukuda
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc.

Keywords: 2-amino-3H-phenoxazin-3-one, nitric oxide, prostaglandin E₂, anti-inflammation, immunomodulation

JOURNAL FREE ACCESS

2008 Volume 31 Issue 10 Pages 1938-1945

DOI https://doi.org/10.1248/bpb.31.1938

Details

Abstract

Accumulating evidence suggests that nitric oxide (NO) and prostaglandin E₂ (PGE₂) are involved in the pathogenesis of various chronic inflammatory diseases and cancer. During the course of a screening program to identify natural anti-inflammatory substances, we isolated the compound 2-amino-3H-phenoxazin-3-one (APO) from an extract of the edible brown mushroom Agaricus bisporus IMBACH. APO inhibited NO production by mouse peritoneal macrophages in response to the pro-inflammatory stimuli lipopolysaccharide (LPS) and interferon (IFN)-γ (LPS/IFN-γ) at low concentrations (IC₅₀=1.5 μM) through reduced inducible NO synthase protein expression. PGE₂ production by LPS/IFN-γ-stimulated macrophages was inhibited by APO at much lower concentrations (IC₅₀=0.27 μM) than those required for the inhibition of NO production. Mechanistic analysis showed that APO inhibited both cyclooxygenase (COX)-1 and COX-2 enzyme activities with almost equal selectivity. Secretion of NO and the pro-inflammatory cytokine IL-6 by IFN-γ-activated RAW264.7 cells, a murine macrophage-like cell line, was also dose-dependently reduced by APO. Furthermore, APO increased the secretion of the anti-inflammatory cytokine IL-4 by antigen-stimulated T cells and promoted the polarization of CD4⁺ Th cells toward the anti-inflammatory Th2 phenotype at equimolar concentrations that inhibited NO production. Our results suggested that APO induced polarization toward the Th2 subset, at least in part through the down-regulation of IL-12 production. Thus, APO appears to have potent anti-inflammatory and immunoregulatory properties that may provide a promising therapeutic strategy for the treatment of T cell-mediated inflammatory autoimmune diseases as well as for bacteria-induced chronic-inflammatory diseases.

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