L161982 alleviates collagen-induced arthritis in mice by increasing Treg cells and down-regulating Interleukin-17 and monocyte-chemoattractant protein-1 levels

Abstract

BackgroundTo investigate the effects and potential mechanism of L161982 (a kind of EP4 antagonist) on the collagen-induced arthritis (CIA) mice model.MethodsThe CIA mice model were first established by immunizing with Chicken Type II Collagen on DBA/1 mice. The CIA groups were administered once a day for 2 weeks with either 5 mg/kg L161982 by intraperitoneal injections (IP), 200 U celecoxib by intragastrical injections, or 100 μl PBS (IP). At the end of the study, total arthritis score and histopathologic examination were assessed to determine CIA severity. The plasma and tissue expressions of IL-17 and monocyte chemoattractant protein-1 (MCP-1) were detected by enzyme-linked immunosorbent assay (ELISA) and Immunohistochemical staining (IHC) respectively; The number of CD4+CD25+Foxp3+ regulatory T cells (Treg) determined as a proportion of total CD4+ cells in the lymph nodes and spleen. We also tested the proliferation of isolated Tregs and the ratio of Th17 polarization of Naïve T cells under the treatment of L161982 by BrdU assay and flow cytometry respectively.ResultsCIA mice treated with L161982 showed reduced arthritis scores, joint swellings, cracked cartilage surface, and less hyperplasia in the connective tissue of the articular cavity. Plasma and tissue IL-17 and MCP-1 decreased, while the proportion of Treg cells is increased both in the spleen and lymph nodes of CIA mice. Otherwise, L161982 have no direct effect on Tregs proliferation; a decreased tendency of Th17 polarization in vitro were observed in L161982-treated naïve T cells.ConclusionAlthough less effective than Celecoxib, L161982 also resulted in a reduction of ankle joint inflammation in CIA mice. L161982 reduces the RA severity in CIA mice through inhibition of IL-17 and MCP-1, increasing Treg cells, and reducing inflammation. The mechanism of the reduction of IL-17 in plasma or tissue after administration of L161982 might be potentially derived from the suppression of CD4+ T cells differentiation into Th-17 cells.Electronic supplementary materialThe online version of this article (10.1186/s12891-017-1819-3) contains supplementary material, which is available to authorized users.

Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF‐β signalling

“…On the other side, PGE 2 has also been reported to suppress Treg cell differentiation and signature gene (e.g. Foxp3, IL-10) expression from both mouse and human effector T cells through direct actions on T cells via EP2 and/or EP4 receptors [32,33,[61][62][63][64]. In agreement with these reports, blocking PG biosynthesis including PGE 2 production by NSAIDs or blocking PGE 2 signalling by an EP4 selective antagonist enhanced Foxp3 expression and iTreg induction, and therefore ameliorated T cell-mediated tissue inflammation [32,[65][66][67].…”

“…Foxp3, IL-10) expression from both mouse and human effector T cells through direct actions on T cells via EP2 and/or EP4 receptors [32,33,[61][62][63][64]. In agreement with these reports, blocking PG biosynthesis including PGE 2 production by NSAIDs or blocking PGE 2 signalling by an EP4 selective antagonist enhanced Foxp3 expression and iTreg induction, and therefore ameliorated T cell-mediated tissue inflammation [32,[65][66][67]. Moreover, we have recently found that PGE 2 inhibits Treg cell expansion or accumulation in the intestine through T cell-independent but microbiotadependent mechanisms [35].…”

“…Importantly, emergent studies using pharmacological approaches and transgenic animal modelsthat target PGE 2 receptors have demonstrated that the actions of PGE 2 on T cells promote immune-associated chronic inflammatory diseases in rodents and humans (including multiple sclerosis, rheumatoid arthritis, inflammatory skin and gut inflammation) [24][25][26][27][28][29][30]. While PGE 2 was initially described to facilitate iTreg cell differentiation in vitro [31], it has also been reported to inhibit Foxp3 induction and reduce Treg cell numbers [32][33][34]. We have recently reported a T cell-independent function of PGE 2 on facilitation of Foxp3 + Treg cell responses in the intestine [35].…”

Prostaglandin E2directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling

“…Chen et al ., 2010; Esaki et al ., 2010; J. Lee et al ., 2018; Robb et al ., 2017; Schiffmann et al ., 2014; Yao et al ., 2009, 2013), it has also been reported to inhibit Foxp3 induction and reduce Treg cell numbers (L. Chen et al ., 2017; H. Li et al ., 2017; Sahin & Sahin, 2020). We have recently reported a T cell-independent function of PGE 2 on facilitation of Foxp3 + Treg cell responses in the intestine (Crittenden et al ., 2021).…”

“…Chen et al, 2010;Esaki et al, 2010;J. Lee et al, 2018;Robb et al, 2017;Schiffmann et al, 2014;Yao et al, 2009Yao et al, , 2013, it has also been reported to inhibit Foxp3 induction and reduce Treg cell numbers (L. Chen et al, 2017;H. Li et al, 2017;Sahin & Sahin, 2020).…”