Enhancement of collagen‐induced arthritis in mice genetically deficient in extracellular superoxide dismutase

Abstract

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 ␣ (TNF␣) over 48 hours in culture compared with cells from WT mice. Increased steady-state levels of messenger RNA (mRNA) for interferon-␥ (IFN␥), TNF␣, and interleukin-1␤ (IL-1␤), 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.Conclusion. The absence of EC-SOD leads to more severe CIA, which may be accompanied by enhanced production of the proinflammatory cytokines IFN␥, TNF␣, and IL-1␤, and decreased production of the antiinflammatory cytokine IL-1Ra in the joints.

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…In that case, a deficiency in the generation of reactive oxygen species results in reduced IDO activity and, similar to our observations in CIA, bypassing the requirements for IDO activation through the administration of L-kynurenine or other tryptophan metabolites restored a functional kynurenine pathway and ameliorated disease (16,29). Interestingly, although it is well accepted that the production of reactive oxygen species in the rheumatoid joint is associated with increased arthritis severity (30,31), a specific deficiency in the production of reactive oxygen species by myeloid cells in the lymph nodes promotes T cell hyperactivation and exacerbates CIA (32). These findings indicate that the activation of IDO is the limiting step in the production of tryptophan metabolites and suggests that other enzymes of the kynurenine pathway are functional during CIA.…”

Interleukin‐1 in combination with oncostatin M up‐regulates multiple genes in chondrocytes: Implications for cartilage destruction and repair

“…Another protein that may have a protective role is superoxide dismutase, which is an antioxidant that removes superoxide anions that have been implicated in hyaluronic acid and cartilage ECM damage. The role of this protein is supported by evidence showing that a genetic deficiency in superoxide dismutase results in an enhancement of collageninduced arthritis in mice (50).…”

B Cell Depletion Delays Collagen-Induced Arthritis in Mice: Arthritis Induction Requires Synergy between Humoral and Cell-Mediated Immunity

“…Tissue sections (5 m) were stained with H&E for microscopic evaluation. Degrees of synovial hyperplasia, cartilage damage, bone erosion, and ankylosis were each assessed in a blinded fashion with the severity of each disease parameter graded in joint sections using a scoring system from 0 to 5: 0, within normal limits; 1, minimal; 2, mild; 3, moderate; 4, marked; 5, severe as described (46).…”