title: Endogenous IL-22 plays a dual role in arthritis: regulation of established arthritis via IFN-γ responses.
abstract: OBJECTIVE
  IL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis.
  
  
  METHODS
  Collagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR.
  
  
  RESULTS
  Collagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity.
  
  
  CONCLUSIONS
  We show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN-γ responses. IL-17 responses remained unchanged with the administration of anti-IL22 antibody. IL-22R1 is upregulated on CD4+T cells during arthritis and regulates IFN-γ in T cells.
authors.affiliation: Section of Rheumatology, Department of Medicine, and the Arizona Arthritis Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Shivali
authors.initials: S
authors.lastname: Justa
authors.affiliation: Section of Rheumatology, Department of Medicine, and the Arizona Arthritis Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Section of Rheumatology, Department of Medicine, and the Arizona Arthritis Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003094:Collagen; D005260:Female; D005620:Freund's Adjuvant; D005786:Gene Expression Regulation / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D057134:Antibodies, Neutralizing; D003094:Collagen; D005620:Freund's Adjuvant; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C415369:interleukin-22 receptor