Down-regulation of lipoxin A4 receptor by thromboxane A2 signaling in RAW246.7 cells in vitro and bleomycin-induced lung fibrosis in vivo

Biomed Pharmacother. Jul-Aug 2004;58(6-7):381-7. doi: 10.1016/j.biopha.2004.05.006.

Abstract

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 A4 (LXA4) as "braking signals" is mediated by the receptor. On the other hand, thromboxane A2 (TXA2) 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 TXA2 receptor (TP) and LXA4 receptor, effects of a TP agonist and a thromboxane synthetase inhibitor on expression of LXA4 receptor were examined in vitro and in vivo. A TP agonist, U46619 showed a down-regulation of LXA4 receptor induced by interleukin-1beta (IL-1beta) in RAW246.7 cells. In bleomycin-induced lung fibrosis in mice, administration of a thromboxane synthetase inhibitor DP-1904 increased LXA4 receptor mRNA and decreased type I collagen mRNA. In vitro experiments indicate that LXA4 significantly prevented enhanced proliferation of NIH3T3 fibroblasts and the collagen expression by transforming growth factor-beta (TGF-beta). These results suggest that TXA2-TP signaling could cause negative regulation of lipoxin A4 receptor under the transcriptional level during inflammatory process mediated by IL-1beta and TGF-beta induce the expression of LXA4 receptor. Furthermore, the down-regulation of LXA4 receptor by TXA2 implies a possibility that a cellular signaling by TXA2 may have a novel and potential function as a pro-inflammatory factor to inhibit anti-inflammatory effect of LXA4. Concomitantly, selective blockade of TXA2-TP signaling could be suggested to lead to anti-inflammation through active role of LXA4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Animals
  • Bleomycin
  • Cell Line
  • Cell Proliferation / drug effects
  • Collagen Type I / antagonists & inhibitors
  • Collagen Type I / biosynthesis
  • Collagen Type I / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Interleukin-1 / biosynthesis
  • Lipoxins / metabolism*
  • Lung / drug effects
  • Lung / metabolism
  • Mice
  • NIH 3T3 Cells
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • RNA, Messenger / biosynthesis
  • Receptors, Lipoxin / biosynthesis*
  • Receptors, Lipoxin / genetics
  • Receptors, Thromboxane A2, Prostaglandin H2 / agonists*
  • Receptors, Thromboxane A2, Prostaglandin H2 / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrahydronaphthalenes / pharmacology
  • Transforming Growth Factor beta / biosynthesis
  • Vasoconstrictor Agents / pharmacology

Substances

  • Collagen Type I
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-1
  • Lipoxins
  • RNA, Messenger
  • Receptors, Lipoxin
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Tetrahydronaphthalenes
  • Transforming Growth Factor beta
  • Vasoconstrictor Agents
  • lipoxin A4
  • Bleomycin
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • nafagrel