title: Transcriptional profiling of liver and effect of glucocorticoids in a rat adjuvant-induced arthritis model.
abstract: Glucocorticoids (GCs), despite having many undesirable side effects, remain effective for the treatment of many inflammatory diseases and are commonly used as benchmark drugs in animal models of disease. However, the molecular mechanisms underling systemic GC effects in these models are poorly characterized. In this study, prednisolone and dexamethasone were evaluated in the fully established Lewis rat adjuvant-induced arthritis (AIA) model. In AIA, adjuvant administration induced polyarticular and systemic inflammation, which included spleen and liver. In the liver, multifocal hepatic granulomas were observed. To characterize the systemic response and the pathways responsible for GC effects, histology, transcriptional profiling, and immunohistochemistry (IHC) were performed. There was a decrease in the incidence and histologic severity score for granulomas with GC treatment. There was no effect on cellular composition of granulomas as assessed by IHC for CD3+ lymphocytes, macrophages, and B cells, but there was a significant reduction in infiltrating lymphocytes in the hepatic parenchyma. By Affymetrix microarray analysis, 10% of hepatic transcripts were altered (P<.01) in livers from AIA rats, with ~31% of them partially reversed with treatment with dexamethasone and ~13% with prednisolone. Many of these altered hepatic transcripts correspond to human genes that are dysregulated in the synovium in human rheumatoid arthritis (RA), indicating that the rat AIA model shares features with human RA. These data establish molecular changes in the liver and the effect of GCs in rat AIA, which can be used to aid in understanding the mechanism of action of novel anti-inflammatory compounds in this animal model.
authors.affiliation: Department of Discovery Toxicology, Bristol-Myers Squibb, Princeton, NJ 08450, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Song
authors.forename: W R
authors.initials: WR
authors.lastname: Foster
authors.forename: D J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: S G
authors.initials: SG
authors.lastname: Nadler
authors.forename: L
authors.initials: L
authors.lastname: Salter-Cid
authors.forename: V G
authors.initials: VG
authors.lastname: Sasseville
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism*; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D011239:Prednisolone