title: Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines.
abstract: In animal models of arthritis induced with Ags or infectious agents, disease severity correlates with a dominant Th1-type response characterized by a higher ratio of IFN-gamma to IL-4. Analysis of BALB/c mice revealed a genetic predisposition toward developing CD4+ Th2-type responses. The bias toward an IL-4-dominant response in BALB/c mice protects mice from severe Lyme-induced arthritis and spontaneous autoimmune disease. Since BALB/c mice immunized with proteoglycan develop severe arthritis, we were interested in testing whether arthritis is associated with a Th2-type response and thus is different from other arthritic models. BALB/c mice immunized with proteoglycan generated a higher ratio of IFN-gamma to IL-4 that peaks at the onset of arthritis. We investigated whether when Th1 cells were dominant, disease outcome could be modified with pharmacological amounts of Th2 cytokines. Treatment with IL-4 prevented disease and induced a switch from a Th1-type to a Th2-type response. Proinflammatory cytokine mRNA transcripts were reduced in joints of cytokine-treated mice. Th2 cytokine therapy at the time of maximum joint inflammation also suppressed symptoms of disease. Despite the predisposition of BALB/c mice to a Th2-type response, proteoglycan-induced arthritis is a Th1-type disease. The effectiveness of IL-4 treatment was particularly striking because in other models of arthritis, treatment in a similar manner with IL-4 was not sufficient to inhibit arthritis. The effective control of arthritis and the switch from a Th1 to Th2 response suggest that levels of endogenous IL-4 in BALB/c mice may increase their responsiveness to Th2 cytokine therapy.
authors.affiliation: Department of Medicine, Section of Rheumatology, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. afinnega@rush.edu
authors.forename: A
authors.initials: A
authors.lastname: Finnegan
authors.forename: K
authors.initials: K
authors.lastname: Mikecz
authors.forename: P
authors.initials: P
authors.lastname: Tao
authors.forename: T T
authors.initials: TT
authors.lastname: Glant
mesh_terms: D000208:Acute Disease; D053674:Aggrecans; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology* / Q000627:therapeutic use; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D007114:Immunization; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D037181:Lectins, C-Type; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D053674:Aggrecans; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007371:Interferon-gamma; D015847:Interleukin-4; D015850:Interleukin-6; D037181:Lectins, C-Type; D008233:Lymphotoxin-alpha; D011509:Proteoglycans; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C508320:Acan protein, mouse