Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice.

Autor: Luo Y; University of California, San Diego at La Jolla., Boyle DL, Hammaker D, Edgar M, Franzoso G, Firestein GS
Jazyk: angličtina
Zdroj: Arthritis and rheumatism [Arthritis Rheum] 2011 Oct; Vol. 63 (10), pp. 2949-55.
DOI: 10.1002/art.30497
Abstrakt: 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.
Conclusion: 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.
(Copyright © 2011 by the American College of Rheumatology.)
Databáze: MEDLINE
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