Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor

OBJECTIVE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage CSF (M-CSF or CSF-1) are involved in the methylated bovine serum albumin/interleukin-1 (mBSA/IL-1)-induced arthritis model. METHODS: Following systemic injection, IL-1 has been shown to augment a weak inflammatory response to mBSA in murine joints and to induce an acute erosive arthritis. GM-CSF and M-CSF have been implicated in inflammatory reactions, including those in joints, and have recently been shown to exacerbate murine arthritis. Since in vitro studies have found that IL-1 can enhance GM-CSF and M-CSF production, we reasoned that they might be playing a part in IL-1-mediated arthritis. GM-CSF-deficient (GM-CSF-/-) and M-CSF-deficient (op/op) mice were injected intraarticularly with mBSA and subcutaneously with IL-1. Arthritis was monitored histologically on day 7. Normal mice were also treated intraperitoneally with blocking monoclonal antibodies to GM-CSF and M-CSF, and to the M-CSF receptor. Numbers of macrophages (Mac-2 and F4/80 staining) were monitored, as was the number of cycling (bromodeoxyuridine-positive) cells. RESULTS: GM-CSF-/- mice and normal mice treated with anti-GM-CSF antibody did not show IL-1-induced arthritis progression. There was a dramatic reduction in synovial cellularity, including reduced numbers of macrophages and cycling cells. The op/op mice did not develop mBSA/IL-1-induced disease, but blocking antibody to M-CSF or to the M-CSF receptor failed to diminish disease in normal mice. CONCLUSION: GM-CSF is involved in the IL-1-induced arthritis that follows mBSA injection; M-CSF involvement in the model is also suggested, since op/op mice did not develop arthritis. These studies provide the first in vivo evidence for a role of GM-CSF, and possibly M-CSF, in the proinflammatory actions of IL-1.