title: Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis.
abstract: T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4+helper T (Th) cell and CD8+cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1β, TNF-α and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway.
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Qingtong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Longsheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Emergency Center, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Wuyi
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054428:Chemokine CX3CL1 / Q000097:blood; D004195:Disease Models, Animal; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; C000594089:IL1B protein, rat; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D017374:Paroxetine; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D008727:Methotrexate