Yb. Guedez et al., Genetic ablation of interferon-gamma up-regulates interleukin-1 beta expression and enables the elicitation of collagen-induced arthritis in a nonsusceptible mouse strain, ARTH RHEUM, 44(10), 2001, pp. 2413-2424
Objective. To determine whether the lack of interferon-gamma (IFN-gamma) al
ters resistance to collagen-induced arthritis (CIA) in a nonsusceptible mou
se strain, and if so, to identify changes in the antibody, cellular type II
collagen (CII)-specific immune responses, and cytokine gene expression tha
t might account for the altered susceptibility.
Methods. CIA-resistant C57BL/6 and C57BL/6 IFN gamma (-/-) mice were immuni
zed with bovine CII in Freund's complete adjuvant (CFA) or in CFA alone. An
imals were monitored for signs of arthritis for up to 80 days; arthritis se
verity was assessed visually and histologically. Sera were collected at var
ious time points after immunization for measurement of anti-CII antibody le
vels. T cell responses to bovine CII were assessed in proliferation assays.
Cytokine messenger RNA (mRNA) expression in lymph node cells and in synovi
al cells from arthritic paws was measured by RNase protection assays, and l
evels of cytokine protein production were determined by enzyme-linked immun
Results. IFN gamma (-/-) mice developed a severe auto-immune arthritis that
was dependent on immunization with CII IFN gamma (-/-) mice produced signi
ficantly higher amounts of IgG1 and IgG2b antibody to the autoantigen, muri
ne CII, compared with wild-type C57BL/6 mice and had an enhanced T cell pro
liferative response to bovine CII Enhanced production of mature interleukin
-1/beta (IL-1 beta) protein was observed, but no significant changes in Th1
or Th2 cytokines. Although IL-6 and tumor necrosis factor a transcripts we
re clearly evident in the synovial cells from the arthritic paws of IFN gam
ma (-/-) mice, neither message was elevated to the levels measured for IL-1
beta expression. Treatment of IFN gamma (-/-) mice with anti-IL-1 beta sig
nificantly reduced the incidence and severity of the inflammation.
Conclusion. Endogenous IFN gamma plays a role in the regulation of IL-1 bet
a in this model of autoimmune arthritis.