Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha transgenic mice

To study the effects of IL-1 alpha in arthritis, we generated human IL-1 al pha (hIL-1 alpha), Transgenic mice expressed hIL-1 alpha mRNA in various or gans, had high serum levels of hIL-1 alpha, and developed a severe polyarth ritic phenotype at 4 weeks of age. Not only bone marrow cells but also syno viocytes from knee joints produced biologically active hIL-1 alpha. Synovit is started 2 weeks after birth, and 8-week-old mice showed hyperplasia of t he synovial lining layer, the formation of hyperplastic synovium (pannus) a nd, ultimately, destruction of cartilage. Hyperplasia of the synovial linin g was due to the accumulation of macrophage-like cells expressing F4/80 mol ecules. hIL-1 alpha was widely distributed in macrophage- and fibroblast-li ke cells of the synovial lining cells, as well as synovial fluid monocytes, T and B cells were rare in the synovial fluid, and analysis of marker expr ession suggests that synoviocytes were directly histolytic and did not act as antigen-presenting cells. In the joints of these mice, we found elevated levels of cells of the monocyte/macrophage and granulocyte lineages and of polymorphonuclear neutrophils (PMNs), most of which expressed Gr-l, indica ting that they were mature, tissue-degrading PMNs. Cultured synoviocytes an d PMNs from these animals overexpress GM-CSF, suggesting that the hematopoi etic changes induced by IL-1 and the consequent PMN activation and joint de struction are mediated by this cytokine.