title: Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice.
abstract: OBJECTIVE
  Growth arrest and DNA damage-inducible protein 45β (GADD45β) is involved in stress responses, cell cycle regulation, and oncogenesis. Previous studies demonstrated that GADD45β deficiency exacerbates K/BxN serum-induced arthritis and experimental allergic encephalomyelitis (EAE) in mice, indicating that GADD45β plays a suppressive role in innate and adaptive immune responses. To further understand how GADD45β regulates autoimmunity, we evaluated collagen-induced arthritis in GADD45β-/- mice.
  
  
  METHODS
  Wild-type (WT) and GADD45β-/- DBA/1 mice were immunized with bovine type II collagen (CII). Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. Expression of cytokines and matrix metalloproteinases in the joint and spleen was determined by quantitative polymerase chain reaction. The in vitro T cell cytokine response to CII was measured by multiplex analysis. CD4+CD25+ Treg cells and Th17 cells were quantified using flow cytometry.
  
  
  RESULTS
  GADD45β-/- mice showed significantly lower arthritis severity and joint destruction compared with WT mice. MMP-3 and MMP-13 expression was also markedly reduced in GADD45β-/- mice. However, serum anti-CII antibody levels were similar in both groups. FoxP3 and interleukin-10 (IL-10) expression was increased 2-3-fold in splenocytes from arthritic GADD45β-/- mice compared with those from WT mice. Flow cytometric analysis showed greater numbers of CD4+CD25+ Treg cells in the spleen of GADD45β-/- mice than in the spleen of WT mice. In vitro studies showed that interferon-γ and IL-17 production by T cells was significantly decreased in GADD45β-/- mice.
  
  
  CONCLUSIONS
  Unlike passive K/BxN arthritis and EAE, GADD45β deficiency in CIA was associated with lower arthritis severity, elevated IL-10 expression, decreased IL-17 production, and increased numbers of Treg cells. The data suggest that GADD45β plays a complex role in regulating adaptive immunity and, depending on the model, either enhances or suppresses inflammation.
authors.affiliation: University of California, San Diego at La Jolla.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Luo
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.forename: Deepa
authors.initials: D
authors.lastname: Hammaker
authors.forename: Meghan
authors.initials: M
authors.lastname: Edgar
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D051858:Forkhead Transcription Factors; D016753:Interleukin-10; C498833:Foxp3 protein, mouse; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins