RESUMEN
BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. EXPERIMENTAL APPROACH: Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. KEY RESULTS: Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. CONCLUSION AND IMPLICATIONS: PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Benzazepinas/farmacología , Imidazoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Administración Oral , Animales , Artritis Experimental/fisiopatología , Artritis Reumatoide/fisiopatología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Colágeno , Modelos Animales de Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Endogámicas F344 , Subtipo EP4 de Receptores de Prostaglandina E , Transducción de Señal/efectos de los fármacos , Células TH1/efectos de los fármacosRESUMEN
With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.