title: Aryl hydrocarbon receptor antagonism attenuates growth factor expression, proliferation, and migration in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease with high morbidity and mortality. Within the inflammatory milieu, resident fibroblast-like synoviocytes (FLS) in the synovial tissue undergo hyperplasia, which leads to joint destruction. Epidemiologic studies and our previous research suggest that activation of the aryl hydrocarbon receptor (AHR) pathway plays an instrumental role in the inflammatory and destructive RA phenotype. In addition, our recent studies implicate the AHR in the regulation of the expression of several growth factors in established tumor cell lines. Thus, under inflammatory conditions, we hypothesized that the AHR is involved in the constitutive and inducible expression of several growth factors, FLS proliferation and migration, along with protease-dependent invasion in FLS from patients with RA (RA-FLS). Treatment with the AHR antagonist GNF351 inhibits cytokine-induced expression of vascular endothelial growth factor-A (VEGF-A), epiregulin, amphiregulin, and basic fibroblast growth factor mRNA through an AHR-dependent mechanism in both RA-FLS and FLS. Secretion of VEGF-A and epiregulin from RA-FLS was also inhibited upon GNF351 treatment. RA-FLS cell migration, along with cytokine-induced RA-FLS cell proliferation, was significantly attenuated by GNF351 exposure. Treatment of RA-FLS with GNF351 mitigated cytokine-mediated expression of matrix metalloproteinase-2 and -9 mRNA and diminished the RA-FLS invasive phenotype. These findings indicate that inhibition of AHR activity may be a viable therapeutic target in amelioration of disease progression in RA by attenuating growth factor release; FLS proliferation, migration, and invasion; and inflammatory activity.
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (T.S.L., J.M.H., A.K., B.Z., I.A.M., J.M.P., G.H.P.); DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware (K.J.); and Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania (K.G., S.G.A.).
authors.forename: Tejas S
authors.initials: TS
authors.lastname: Lahoti
authors.forename: Jarod M
authors.initials: JM
authors.lastname: Hughes
authors.forename: Ann
authors.initials: A
authors.lastname: Kusnadi
authors.forename: Kaarthik
authors.initials: K
authors.lastname: John
authors.forename: Bokai
authors.initials: B
authors.lastname: Zhu
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
mesh_terms: D066258:Amphiregulin; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D018501:Antirheumatic Agents; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066260:Epiregulin; D016222:Fibroblast Growth Factor 2; D018093:Gelatinases; D006023:Glycoproteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D011687:Purines; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C111235:AHR protein, human; C587848:AREG protein, human; C587880:EREG protein, human; C508585:IL1B protein, human; C560625:N-(2-(3H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methyl-3-pyridyl)purin-6-amine; C467484:VEGFA protein, human