Down-regulation of lipoxin A 4 receptor by thromboxane A 2 signaling in RAW246.7 cells in vitro and bleomycin-induced lung fibrosis in vivo

• Published in: Biomedicine & pharmacotherapy Vol. 58; no. 6; pp. 381 - 387
• Main Authors: Sato, Yoshinori, Kitasato, Hidero, Murakami, Yousuke, Hashimoto, Atsushi, Endo, Hirahito, Kondo, Hirobumi, Inoue, Matsuhisa, Hayashi, Izumi
• Format: Journal Article
• Language: English
• Published: Elsevier SAS 2004
• Subjects: Lipoxin A 4 receptor; Lung fibrosis; Thromboxane A 2; TGF; Thromboxane A 2; IL; TX; RT-PCR; PG; Lipoxin A 4 receptor; LX; Lung fibrosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2004.05.006

Lipoxins (LXs) are members of eicosanoid family that can be endogenously produced during cell-to-cell interactions such as platelet–leukocyte interactions. Anti-inflammatory function of lipoxin A 4 (LXA 4) as “braking signals” is mediated by the receptor. On the other hand, thromboxane A 2 (TXA 2) produced by catalysis of cyclooxygenase and thromboxane synthetase is released during platelet aggregation as a vasoconstrictor and a pro-inflammatory factor. To investigate interaction of TXA 2 receptor (TP) and LXA 4 receptor, effects of a TP agonist and a thromboxane synthetase inhibitor on expression of LXA 4 receptor were examined in vitro and in vivo. A TP agonist, U46619 showed a down-regulation of LXA 4 receptor induced by interleukin-1β (IL-1β) in RAW246.7 cells. In bleomycin-induced lung fibrosis in mice, administration of a thromboxane synthetase inhibitor DP-1904 increased LXA 4 receptor mRNA and decreased type I collagen mRNA. In vitro experiments indicate that LXA 4 significantly prevented enhanced proliferation of NIH3T3 fibroblasts and the collagen expression by transforming growth factor-β (TGF-β). These results suggest that TXA 2-TP signaling could cause negative regulation of lipoxin A 4 receptor under the transcriptional level during inflammatory process mediated by IL-1β and TGF-β induce the expression of LXA 4 receptor. Furthermore, the down-regulation of LXA 4 receptor by TXA 2 implies a possibility that a cellular signaling by TXA 2 may have a novel and potential function as a pro-inflammatory factor to inhibit anti-inflammatory effect of LXA 4. Concomitantly, selective blockade of TXA 2-TP signaling could be suggested to lead to anti-inflammation through active role of LXA 4.