PMID- 29145862 OWN - NLM STAT- MEDLINE DCOM- 20180717 LR - 20181113 IS - 1471-2474 (Electronic) IS - 1471-2474 (Linking) VI - 18 IP - 1 DP - 2017 Nov 16 TI - L161982 alleviates collagen-induced arthritis in mice by increasing Treg cells and down-regulating Interleukin-17 and monocyte-chemoattractant protein-1 levels. PG - 462 LID - 10.1186/s12891-017-1819-3 [doi] LID - 462 AB - BACKGROUND: To investigate the effects and potential mechanism of L161982 (a kind of EP4 antagonist) on the collagen-induced arthritis (CIA) mice model. METHODS: The 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 mul 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 Naive T cells under the treatment of L161982 by BrdU assay and flow cytometry respectively. RESULTS: CIA 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 naive T cells. CONCLUSION: Although 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. FAU - Chen, Liang AU - Chen L AD - Department of Orthopedics, Renmin Hospital of Wuhan University, 9 Zhangzhidong Street, Wuhan, Hubei, 430060, People's Republic of China. FAU - Wu, Xianglei AU - Wu X AD - Laboratory of Immunology, University of Lorraine, Avenue du Morvan, 54511 Vandoeuvre les Nancy, Nancy, France. FAU - Zhong, Jun AU - Zhong J AD - Department of Orthopedics, Renmin Hospital of Wuhan University, 9 Zhangzhidong Street, Wuhan, Hubei, 430060, People's Republic of China. FAU - Li, Dongqing AU - Li D AUID- ORCID: 0000-0001-7878-7200 AD - Department of Microbiology, School of Basic Medical Science, Wuhan University, 185 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China. lidongqing@whu.edu.cn. LA - eng GR - 81101386/National Natural Science Foundation of China/ GR - 30901356/National Natural Science Foundation of China/ GR - 2014CFB158/Natural Science Foundation of Hubei Province, China/ PT - Journal Article DEP - 20171116 PL - England TA - BMC Musculoskelet Disord JT - BMC musculoskeletal disorders JID - 100968565 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Collagen Type II) RN - 0 (Cyclooxygenase 2 Inhibitors) RN - 0 (Interleukin-17) RN - 0 (L-161982) RN - 0 (Ptger4 protein, mouse) RN - 0 (Receptors, Prostaglandin E, EP4 Subtype) RN - 0 (Thiophenes) RN - 0 (Triazoles) RN - JCX84Q7J1L (Celecoxib) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Animals MH - Ankle Joint/drug effects/pathology MH - Arthritis, Experimental/blood/*drug therapy/immunology MH - Arthritis, Rheumatoid/blood/*drug therapy/immunology MH - Celecoxib/pharmacology/therapeutic use MH - Cell Differentiation/drug effects/immunology MH - Cell Proliferation/drug effects MH - Chemokine CCL2/blood/immunology/*metabolism MH - Collagen Type II/immunology MH - Cyclooxygenase 2 Inhibitors/pharmacology/therapeutic use MH - Dinoprostone/metabolism MH - Down-Regulation MH - Female MH - Humans MH - Injections, Intraperitoneal MH - Interleukin-17/blood/immunology/*metabolism MH - Mice MH - Mice, Inbred DBA MH - Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors/metabolism MH - Severity of Illness Index MH - Signal Transduction/drug effects/immunology MH - T-Lymphocytes, Regulatory/*drug effects/immunology MH - Th17 Cells/immunology MH - Thiophenes/*pharmacology/therapeutic use MH - Triazoles/*pharmacology/therapeutic use PMC - PMC5691865 OTO - NOTNLM OT - Collagen-induced arthritis OT - EP4 antagonist OT - Interleukin-17 OT - Monocyte chemotactic protein-1 OT - Rheumatoid arthritis COIS- ETHICS APPROVAL: This study was approved by the animal ethics committee of Renmin Hospital of Wuhan University (Approval number:2,013,127, EXP#S01314040 T), Wuhan, Hubei, China. All animal experiments complied with the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health; HRP: horseradishperoxidase; HSD test: Tukey's Honestly Significant Difference test. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: We declare no conflicts of interest related to this paper. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2017/11/18 06:00 MHDA- 2018/07/18 06:00 PMCR- 2017/11/16 CRDT- 2017/11/18 06:00 PHST- 2017/04/28 00:00 [received] PHST- 2017/11/08 00:00 [accepted] PHST- 2017/11/18 06:00 [entrez] PHST- 2017/11/18 06:00 [pubmed] PHST- 2018/07/18 06:00 [medline] PHST- 2017/11/16 00:00 [pmc-release] AID - 10.1186/s12891-017-1819-3 [pii] AID - 1819 [pii] AID - 10.1186/s12891-017-1819-3 [doi] PST - epublish SO - BMC Musculoskelet Disord. 2017 Nov 16;18(1):462. doi: 10.1186/s12891-017-1819-3.