The interactions between IL-1 and several neuropeptides associated with pain and inflammation were examined in the context of fibroblast proliferation as a paradigm for the synovial hyperplasia associated with chronic rheumatoid arthritis. The BALB/3T3 fibroblast cell line, which proliferates in response to increasing doses of IL-1, demonstrated enhanced proliferation after a 72-h culture period when various neuropeptides were included with IL-1 in serum-free medium. Thus, bradykinin, at concentrations between 10(-8) and 10(-5) M, moderately promoted [3H]TdR incorporation in vitro in the BALB/3T3 cells, and substance P at approximately 3 x 10(-9) to 3 x 10(-7) M demonstrated minor proliferative activity. However, when the cells were cultured with IL-1 plus substance P or IL-1 plus BK, the ensuing proliferative responses, as measured by [3H]TdR incorporation, were consistently magnified greater than or equal to twofold above the anticipated additive response caused by IL-1 in combination with either of those neuropeptides. Combinations of IL-1 and SP, or IL-1 and BK, also provoked increases in cell numbers that did not occur when the mediators were tested individually. In other experiments, we tested neurokinin-A, Neurokinin-B, histamine, and serotonin. These results are discussed with respect to neurogenic contributions to the immunopathology of IL-1-mediated inflammation.

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