title: IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms.
abstract: IL-4, a well-recognized modulator of macrophage activation, is perceived as an anti-inflammatory cytokine; however, under certain circumstances IL-4 may function as a proinflammatory cytokine. We have previously demonstrated that IL-4 treatment of mice with proteoglycan-induced arthritis (PGIA) inhibited the development of disease. To determine whether the capacity of IL-4 to inhibit disease is dependent on IL-4-mediated regulation of IL-12, we assessed the requirement for IL-4 in modulating development of PGIA. Immunization of mice, lacking IL-4 and Stat6, with proteoglycan results in a significant increase in arthritis severity in comparison to wild-type controls, suggesting that arthritis severity is regulated by IL-4 through a Stat6-dependent mechanism. Concomitant with exacerbated disease in IL-4(-/-) mice, there is a significant increase in the systemic production of proinflammatory cytokines IL-12, TNF-alpha, and IFN-gamma and in levels of mRNA transcripts for proinflammatory cytokines and chemokines in joints. Disease is suppressed in Stat4(-/-) mice indicating that elevated levels of IL-12 contribute to exacerbation of arthritis and that suppression is accompanied by reduced levels of IFN-gamma production. In support of this, IFN-gamma(-/-) mice are protected from PGIA and the degree of inflammation is similar to Stat4(-/-) mice. The decrease in disease severity in IFN-gamma(-/-) and Stat4(-/-) mice correlates with diminished TNF-alpha levels but there is no switch to a Th2-type response. Taken together, these results suggest that IL-4 regulates the severity of disease in PGIA by controlling IL-12 production, which in turn regulates the magnitude of IFN-gamma expression through a Stat4-dependent pathway.
authors.affiliation: Section of Rheumatology, Department of Medicine, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. Alison_Finnegan@rush.edu
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: Charles D
authors.initials: CD
authors.lastname: Kaplan
authors.forename: Shannon K
authors.initials: SK
authors.lastname: O'Neill
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.forename: Tamas
authors.initials: T
authors.lastname: Koreny
authors.forename: Matyas
authors.initials: M
authors.lastname: Czipri
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D053674:Aggrecans; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016326:Extracellular Matrix Proteins; D005260:Female; D006614:Hindlimb; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D037181:Lectins, C-Type; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011509:Proteoglycans / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C508320:Acan protein, mouse; D053674:Aggrecans; D001323:Autoantibodies; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma