TY - JOUR
T1 - Suppression by citrus auraptene of phorbol ester- and endotoxin-induced inflammatory responses
T2 - Role of attenuation of leukocyte activation
AU - Murakami, Akira
AU - Nakamura, Yoshimasa
AU - Tanaka, Takuji
AU - Kawabata, Kyuichi
AU - Takahashi, Daisuke
AU - Koshimizu, Koichi
AU - Ohigashi, Hajime
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2000
Y1 - 2000
N2 - Auraptene (AUR), a citrus coumarin derivative, is one of the promising chemopreventive agents against skin, tongue, esophagus and colon carcinogenesis in rodents. We reported previously that AUR suppresses superoxide anion (O2-) generation from inflammatory leukocytes in in vitro experiments. In the present study, we investigated the anti-inflammatory activities of AUR using a 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin model, and compared them with those of umbelliferone (UMB), a structural analog of AUR that is virtually inactive toward O2- generation inhibition. Double pre-treatments of mouse skin with AUR, but not UMB, markedly suppressed edema formation, hydrogen peroxide production, leukocyte infiltration, and the rate of proliferating cell nuclear antigen-stained cells. These inhibitory effects by AUR are attributable to its selective blockade of the activation stage, as revealed by single pre-treatment experiments. In a murine macrophage line, RAW 264.7, AUR significantly attenuated the lipopolysaccharide-induced protein expression of inducible isoforms of both nitric oxide synthase and cyclooxygenase, with decreased production of nitrite anion and prostaglandin E2, and yet suppressed the release of tumor necrosis factor-α. Conversely, UMB did not show any inhibitory effect. This contrasting activity profile between AUR and UMB was rationalized to be a result of their distinct differences in cellular uptake efficiencies, i.e. the geranyloxyl group in AUR was found to play an essential role in incorporation. Thus, our findings indicate that AUR is an effective agent to attenuate the biochemical responsiveness of inflammatory leukocytes, which may be essential for a greater understanding of the action mechanism that underlies its inhibition of inflammation-associated carcinogenesis.
AB - Auraptene (AUR), a citrus coumarin derivative, is one of the promising chemopreventive agents against skin, tongue, esophagus and colon carcinogenesis in rodents. We reported previously that AUR suppresses superoxide anion (O2-) generation from inflammatory leukocytes in in vitro experiments. In the present study, we investigated the anti-inflammatory activities of AUR using a 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin model, and compared them with those of umbelliferone (UMB), a structural analog of AUR that is virtually inactive toward O2- generation inhibition. Double pre-treatments of mouse skin with AUR, but not UMB, markedly suppressed edema formation, hydrogen peroxide production, leukocyte infiltration, and the rate of proliferating cell nuclear antigen-stained cells. These inhibitory effects by AUR are attributable to its selective blockade of the activation stage, as revealed by single pre-treatment experiments. In a murine macrophage line, RAW 264.7, AUR significantly attenuated the lipopolysaccharide-induced protein expression of inducible isoforms of both nitric oxide synthase and cyclooxygenase, with decreased production of nitrite anion and prostaglandin E2, and yet suppressed the release of tumor necrosis factor-α. Conversely, UMB did not show any inhibitory effect. This contrasting activity profile between AUR and UMB was rationalized to be a result of their distinct differences in cellular uptake efficiencies, i.e. the geranyloxyl group in AUR was found to play an essential role in incorporation. Thus, our findings indicate that AUR is an effective agent to attenuate the biochemical responsiveness of inflammatory leukocytes, which may be essential for a greater understanding of the action mechanism that underlies its inhibition of inflammation-associated carcinogenesis.
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U2 - 10.1093/carcin/21.10.1843
DO - 10.1093/carcin/21.10.1843
M3 - Article
C2 - 11023542
AN - SCOPUS:0033782926
VL - 21
SP - 1843
EP - 1850
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 10
ER -