These authors contributed equally to this work.
Lipoxin A4 attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects
Version of Record online: 7 JUL 2010
© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society
British Journal of Pharmacology
Volume 161, Issue 4, pages 911–924, October 2010
How to Cite
Conte, F., Menezes-de-Lima, O., Verri, W., Cunha, F., Penido, C. and Henriques, M. (2010), Lipoxin A4 attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects. British Journal of Pharmacology, 161: 911–924. doi: 10.1111/j.1476-5381.2010.00950.x
- Issue online: 7 JUL 2010
- Version of Record online: 7 JUL 2010
- Accepted manuscript online: 7 JUL 2010 12:00AM EST
- Received17 November 2009Revised9 May 2010Accepted19 May 2010
- acetylsalicylic acid;
- oedema formation;
BACKGROUND AND PURPOSE Lipoxin A4 (LXA4) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA4 in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A4 receptor (FPR2/ALX) in the synovial tissues of rheumatoid arthritis patients have been reported. Endothelins (ETs) play a pivotal pro-inflammatory role in acute articular inflammatory responses. Here, we evaluated the anti-inflammatory role of LXA4, during the acute phase of zymosan-induced arthritis, focusing on the modulation of ET-1 expression and its effects.
EXPERIMENTAL APPROACH The anti-inflammatory effects of LXA4, BML-111 (agonist of FPR2/ALX receptors) and acetylsalicylic acid (ASA) pre- and post-treatments were investigated in a murine model of zymosan-induced arthritis. Articular inflammation was assessed by examining knee joint oedema; neutrophil accumulation in synovial cavities; and levels of prepro-ET-1 mRNA, leukotriene (LT)B4, tumour necrosis factor (TNF)-α and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA4 on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively.
KEY RESULTS LXA4, BML-111 and ASA administered as pre- or post-treatment inhibited oedema and neutrophil influx induced by zymosan stimulation. Zymosan-induced preproET-1 mRNA, KC/CXCL1, LTB4 and TNF-α levels were also decreased after LXA4 pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA4 pretreatment. LXA4 treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints.
CONCLUSION AND IMPLICATION LXA4 exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects.