Lipoxin A 4 Suppresses IL-1β-Induced Cyclooxygenase-2 Expression Through Inhibition of p38 MAPK Activation in Endometriosis

Abstract

Endometriosis is an inflammation-dependent gynecologic disorder. Increased cyclooxygenase-2 (COX-2) expression plays an important role in the development and progression of endometriosis. Lipoxin A₄ (LXA₄) is an endogenous anti-inflammation lipid and showed inhibitory effects on the development of endometriosis; however, the mechanism remains unclear. In this study, the overexpression of COX-2 was observed in ectopic endometrium of endometriosis patients compared to the normal endometrium of controls. Lipoxin A₄ efficiently suppressed IL-1β-induced COX-2 protein expression in ectopic endometriotic stromal cells (ESCs) via its receptor, formyl peptide receptor 2/lipoxin A₄ receptor (FPR2/ALX). Antagonism of FPR2/ALX eliminated the inhibitory effect by LXA₄. IL-1β induced the activation of mitogen-activated protein kinases (MAPKs), which can promote the expression of COX-2. Pretreatment of ESCs with LXA₄ inhibited the phosphorylation of p38 MAPK induced by IL-1β. These findings suggest that inflammation and MAPKs pathways respond for the abnormal expression of COX-2, which can elucidate the pathophysiology of endometriosis. Moreover, LXA₄ suppressed IL-1β-induced COX-2 expression through inhibiting the p38 MAPK signaling protein. This research contributes for better understanding of the cellular and biological events of inflammation and anti-inflammation-mediated regulation in endometriosis.

Keywords

endometriosis COX-2 interleukin-1β p38 MAPK

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References

Giudice

Kao

. Endometriosis. Lancet (London, England). 2004;364(9447):1789–1799.

Takenaka

Taniguchi

Miyakoda

Takai

Terakawa

Harada

. Lipopolysaccharide promoted proliferation and invasion of endometriotic stromal cells via induction of cyclooxygenase-2 expression. Fertil steril. 2010;93(1):325–327.

Binion

Otterson

Rafiee

. Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut. 2008;57(11):1509–1517.

Chishima

Hayakawa

Sugita

, et al. Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am J Reprod Immunol (New York, NY: 1989). 2002;48(1):50–56.

Karck

Reister

Schafer

Zahradnik

Breckwoldt

. PGE2 and PGF2 alpha release by human peritoneal macrophages in endometriosis. Prostaglandins. 1996;51(1):49–60.

Ota

Igarashi

Sasaki

Tanaka

. Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum Reprod (Oxford, England). 2001;16(3):561–566.

Banu

Lee

Speights

Jr Starzinski-Powitz

Arosh

. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology. 2008;149(3):1180–1189.

Matsuzaki

Canis

Darcha

Dallel

Okamura

Mage

. Cyclooxygenase-2 selective inhibitor prevents implantation of eutopic endometrium to ectopic sites in rats. Fertil Steril. 2004;82(6):1609–1615.

Ozawa

Murakami

Tamura

Terada

Yaegashi

Okamura

. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via antiangiogenic activity in severe combined immunodeficiency mice. Fertil Steril. 2006;86(4 Suppl):1146–1151.

10.

Bulun

. Endometriosis. New Engl J Med. 2009;360(3):268–279.

11.

Serhan

Chiang

. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. Brit J Pharmacol. 2008;153(Suppl 1):S200–S215.

12.

Maldonado-Perez

Golightly

Denison

Jabbour

Norman

. A role for lipoxin A4 as anti-inflammatory and proresolution mediator in human parturition. FASEB J. 2011;25(2):569–575.

13.

Serhan

Chiang

Van Dyke

. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–361.

14.

Ryan

Godson

. Lipoxins: regulators of resolution. Curr Opin Pharmacol. 2010;10(2):166–172.

15.

Canny

Lessey

. The role of lipoxin A4 in endometrial biology and endometriosis. Mucosal Immunol. 2013;6(3):439–450.

16.

Serhan

Krishnamoorthy

Recchiuti

Chiang

. Novel anti-inflammatory--pro-resolving mediators and their receptors. Curr Top Med Chem. 2011;11(6):629–647.

17.

Chen

Zhou

Huang

Chen

. 15-Epi-lipoxin A(4) inhibits the progression of endometriosis in a murine model. Fertil steril. 2010;93(5):1440–1447.

18.

Chen

Zhou

Zhu

Chen

. Lipoxin A4 regulates expression of the estrogen receptor and inhibits 17beta-estradiol induced p38 mitogen-activated protein kinase phosphorylation in human endometriotic stromal cells. Fertil steril. 2014;102(1):264–271.

19.

Santulli

Marcellin

Tosti

, et al.

MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis?

Expert Opin Ther Targets. 2015;19(11):1465–1483.

20.

Chen

Zhou

Huang

Chen

. The inhibitory effect of 15-R-LXA4 on experimental endometriosis. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):200–204.

21.

Liu

Lang

. Is abnormal eutopic endometrium the cause of endometriosis? The role of eutopic endometrium in pathogenesis of endometriosis. Med Sci Monit. 2011;17(4):Ra92–99.

22.

Shen

Gao

Ding

Chen

. Is the positivity of estrogen receptor or progesterone receptor different between type 1 and type 2 endometrial cancer? Oncotarget. 2016;8(1):506–511.

23.

Macdonald

Boddy

Denison

Sales

Jabbour

. A role for lipoxin A(4) as an anti-inflammatory mediator in the human endometrium. Reproduction (Cambridge, England). 2011;142(2):345–352.

24.

Zhou

Chen

, et al. Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol. 2014;171(21):4927–4940.

25.

Zidan

Rezk

Alnemr

Abd El Ghany

. COX-2 gene promoter DNA methylation status in eutopic and ectopic endometrium of Egyptian women with endometriosis. J Reprod Immunol. 2015;112:63–67.

26.

Johnson

. Defining MAPK interactomes. ACS chem biol. 2011;6(1):18–20.

27.

Yoshino

Osuga

Hirota

, et al. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol. (New York, NY: 1989). 2004;52(5):306–311.

28.

Carli

Metz

Al-Abed

Naccache

Akoum

. Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage migration inhibitory factor: involvement of novel kinase signaling pathways. Endocrinology. 2009;150(7):3128–3137.

29.

Huang

Cao

Liu

Zou

Yin

. MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stromal cells in vitro. Int J Clin Exp Pathol. 2013;6(10):2129–2136.

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