title: Increased expression of beta-arrestin 1 and 2 in murine models of rheumatoid arthritis: isoform specific regulation of inflammation.
abstract: Pro-inflammatory cytokines and chemokines play critical roles in autoimmune diseases including rheumatoid arthritis (RA). Recently, it has been reported that β-arrestin 1 and 2 are involved in the regulation of inflammation. We hypothesized that β-arrestin 1 and 2 play critical roles in murine models of RA. Using a collagen-induced arthritis (CIA) and a human TNFα transgenic (TNFtg) mouse model, we demonstrated that β-arrestin 1 and 2 expression are significantly increased in joint tissue of CIA mice and TNFtg mice. In fibroblast-like synoviocytes (FLS) isolated from hind knee joint of CIA mice, we observed an increase of β-arrestin 1 and 2 protein and mRNA levels in the early stage of arthritis. In FLS, low molecular weight hyaluronan (HA)-induced TNFα and IL-6 production was increased by overexpression of β-arrestin 1 but decreased by overexpression of β-arrestin 2 demonstrating isoform specific regulation. TNFα and HA induced an increase of β-arrestin 1 and 2 expression in FLS, while high mobility group box (HMGB)-1 only stimulated β-arrestin 1 expression. TNFα- or HA-induced β-arrestin 2 expression was blocked by a p38 inhibitor. To examine the in vivo role of β-arrestin 2 in the pathogenesis of arthritis, WT and β-arrestin 2 KO mice were subjected to collagen antibody-induced arthritis (CAIA). β-Arrestin 2 KO mice exhibited more severe arthritis in CAIA. Thus β-arrestin 2 is anti-inflammatory in CAIA. These composite observations suggest that β-arrestin 1 and 2 differentially regulate FLS inflammation and increased β-arrestin 2 may reduce experimental arthritis severity.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States. lippe@musc.edu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Li
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Luttrell
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Keith T
authors.initials: KT
authors.lastname: Borg
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Fan
mesh_terms: D000818:Animals; D019390:Arrestins / Q000096:biosynthesis* / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins