Genetic ablation of interferon-gamma up-regulates interleukin-1beta expression and enables the elicitation of collagen-induced arthritis in a nonsusceptible mouse strain.
OBJECTIVE
To determine whether the lack of interferon-gamma (IFNgamma) alters resistance to collagen-induced arthritis (CIA) in a nonsusceptible mouse strain, and if so, to identify changes in the antibody, cellular type II collagen (CII)-specific immune responses, and cytokine gene expression that might account for the altered susceptibility.


METHODS
CIA-resistant C57BL/6 and C57BL/6 IFNgamma-/- mice were immunized with bovine CII in Freund's complete adjuvant (CFA) or in CFA alone. Animals were monitored for signs of arthritis for up to 80 days; arthritis severity was assessed visually and histologically. Sera were collected at various time points after immunization for measurement of anti-CII antibody levels. T cell responses to bovine CII were assessed in proliferation assays. Cytokine messenger RNA (mRNA) expression in lymph node cells and in synovial cells from arthritic paws was measured by RNase protection assays, and levels of cytokine protein production were determined by enzyme-linked immunosorbent assay.


RESULTS
IFNgamma-/- mice developed a severe autoimmune arthritis that was dependent on immunization with CII. IFNgamma-/- mice produced significantly higher amounts of IgG1 and IgG2b antibody to the autoantigen, murine CII, compared with wild-type C57BL/6 mice and had an enhanced T cell proliferative response to bovine CII. Enhanced production of mature interleukin-1/beta (IL-1beta) protein was observed, but no significant changes in Th1 or Th2 cytokines. Although IL-6 and tumor necrosis factor alpha transcripts were clearly evident in the synovial cells from the arthritic paws of IFNgamma-/- mice, neither message was elevated to the levels measured for IL-1beta expression. Treatment of IFNgamma-/- mice with anti-IL-1beta significantly reduced the incidence and severity of the inflammation.


CONCLUSIONS
Endogenous IFNgamma plays a role in the regulation of IL-1beta, in this model of autoimmune arthritis.
Guedez
Y B
YB
University of Tennessee, Memphis, USA.
Whittington
K B
KB
Clayton
J L
JL
Joosten
L A
LA
van de Loo
F A
FA
van den Berg
W B
WB
Rosloniec
E F
EF
D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000276:immunology; D002417:Cattle; D003094:Collagen / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D015854:Up-Regulation
D007375:Interleukin-1; D007371:Interferon-gamma; D003094:Collagen