Anti-inflammation therapy by activation of prostaglandin EP4 receptor in cardiovascular and other inflammatory diseases

Abstract

Prostaglandin E2 constitutes a major cyclooxygenase-2-derived prostanoid produced at inflammatory sites. In vitro and in vivo data support its role as a modulator of inflammation. Prostaglandin E2 exerts anti-inflammatory effects by binding to one of its receptors, the prostaglandin E receptor 4 (EP4), thereby modulating macrophage and T lymphocyte functions that participate crucially in innate and adaptive immunity and tissue remodeling and repair. The activation of EP4 suppresses the release of cytokines and chemokines from macrophages and T cells, inhibits the proliferation and the activation of T cells, and induces T-cell apoptosis. Lack of EP4 in bone marrow-derived cells accelerates local inflammation in atherosclerotic and aneurysm lesions and increases the prevalence of aneurysm formation. An EP4 agonist promotes graft survival in allograft cardiac transplantation and dampens tissue damage after myocardial ischemia. Anti-inflammatory actions of EP4 agonism may benefit other inflammatory disorders, including colitis and gastric ulcers. By contrast, EP4 acts as a proinflammatory mediator in encephalomyelitis, skin inflammation, and arthritis by promoting T helper (Th) 1 differentiation and Th17 expansion. Overall, EP4 activation produces powerful anti-inflammatory responses in many experimental diseases, rendering EP4 agonists attractive agents to attenuate syndromes associated with inflammation.

Figure 1

Metabolism of arachidonic acid into specific prostanoids. COX-1= cyclooxygenase 1; COX-2 = cyclooxygenase 2; PGIS = prostacyclin synthase; TXS = thromboxane synthase; cPGES = cytosolic prostaglandin E synthase; mPGES-1 = microsomal prostaglandin E synthase 1; mPGES-2 = microsomal prostaglandin E synthase 2; PGDS = prostaglandin D synthase; PGFS = prostaglandin F synthase.

Figure 2

Schematic representation of the EP4-mediated classical pathway and the EP4-mediated anti-inflammatory pathway. Classical pathway: Prostaglandin E₂ through EP4 transiently increases intracellular cAMP (by activation of adenylyl cyclase). cAMP activates protein kinase A (PKA), which subsequently phosphorylates the downstream cAMP response element-binding protein (CREB), which binds to certain DNA sequences and increases the transcription of downstream genes. Anti-inflammatory pathway: EPRAP binds directly to the cytoplasmic tail of EP4 and associates with p105. The EPRAP-p105 complex suppresses NFκB and MEK activation by inhibiting p105 phosphorylation and its degradation, thereby reducing pro-inflammatory gene expression.

Figure 3

Schematic representation of the proposed bi-modal effect of prostaglandin E₂. In the presence of certain modulators, such as IL-12 or IL-23, a low concentration of prostaglandin E₂ results in pro-inflammatory signals. Conversely, a high concentration of prostaglandin E₂ leads to anti-inflammatory responses. Modulators such as L-ornithine decrease proliferation of CD8+ T cells, thereby preventing anti-inflammatory action.