Enhancement of collagen-induced arthritis in mice genetically deficient in extracellular superoxide dismutase.
OBJECTIVE
To examine the influence of superoxide on the severity of collagen-induced arthritis (CIA) in mice.


METHODS
CIA was induced in DBA/1J mice lacking the extracellular superoxide dismutase (EC-SOD) gene (knockout [KO]) and in normal DBA/1J mice (wild-type [WT]).


RESULTS
The clinical disease activity score was significantly higher in EC-SOD-KO mice than in WT mice between days 36 and 53, and the histologic scores for joint damage on day 53 increased 2-fold or more in the EC-SOD-KO mice. There were no significant differences between the 2 groups of mice in proliferation indices of spleen or lymph node cells in vitro after stimulation with type II collagen. Although both IgG1 and IgG2a anticollagen antibody levels increased in both groups of mice between days 21 and 53, there were no significant differences between the 2 groups. Lipopolysaccharide-stimulated spleen cells from EC-SOD-KO mice produced greater levels of tumor necrosis factor alpha (TNFalpha) over 48 hours in culture compared with cells from WT mice. Increased steady-state levels of messenger RNA (mRNA) for interferon-gamma (IFNgamma), TNFalpha, and interleukin-1beta (IL-1beta), and lower levels of IL-1 receptor antagonist (IL-1Ra) mRNA were present in the joints of the EC-SOD-KO mice compared with the WT mice.


CONCLUSIONS
The absence of EC-SOD leads to more severe CIA, which may be accompanied by enhanced production of the proinflammatory cytokines IFNgamma, TNFalpha, and IL-1beta, and decreased production of the antiinflammatory cytokine IL-1Ra in the joints.
Ross
Aron D
AD
National Jewish Medical and Research Center, Denver, Colorado, USA.
Banda
Nirmal K
NK
Muggli
Michele
M
Arend
William P
WP
D000818:Animals; D000917:Antibody Formation; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D045604:Extracellular Fluid / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D024043:Collagen Type II; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013482:Superoxide Dismutase