Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis

Objective. To examine the molecular and cellular mechanisms in a model of a cute inflammatory monarticular arthritis induced by methylated bovine serum albumin (mBSA) and interleukin-1 (IL-1). Methods. Mice were injected intraarticularly with mBSA on day 0 and subcuta neously with recombinant human IL-1 beta on days 0-2. At day 7, knee joints were removed and assessed histologically. Flow cytometry and RNase protect ion were used to analyze IL-1-dependent events. Results. C57BL/6 (B6), 129/Sv, and (B6 x 129/Sv)F-1 hybrid mice, all H-2(b) strains, were susceptible to mBSA/IL-1-induced arthritis, whereas C3H/HeJ (H-2(k)) mice were not. B6 mice lacking T and B cells (RAG-1(-/-)) or major histocompatibility complex (MHC) class II antigens (MHCII-/-), and B6 mice treated with a CD4+ T cell-depleting monoclonal antibody, were resistant t o disease. In contrast, B cell-deficient (mu MT/mu MT) mice developed arthr itis at an incidence and severity similar to that of controls. ReIB-deficie nt (ReIB-/-) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity. In B6 mice, flow cytometry demonstrated an IL-1-dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA (mRNA) for the chemokines monocyte chemoattractant protein 1, macrophage inhibitory prote in 2 (MIP-2), RANTES, MIP-1 alpha, and MIP-1 beta, in vivo and in vitro. Conclusion. Arthritis induced by mBSA/IL-1 is strain specific and dependent on CD4+ T lymphocytes and at least partially on ReIB, but not on B lymphoc ytes or antibody. IL-1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells. This mod el of acute monarticular arthritis is particularly suitable for further inv estigations into cell-mediated immunity in arthritis and the role of IL-1.