OBJECTIVE: The inflammatory mediator substance P (SP) acts principally through the neurokinin (NK1) receptor. We assessed the influence of SP on production of NO and its possible role in the pathogenesis of rheumatoid arthritis (RA). METHODS: The effect of SP (0.1-100 nM) on concentrations of the NO metabolite, nitrite, produced by synovial fibroblasts from RA patients was studied. For comparison, the effects of TNF-alpha (0.57 pM-5.7 nM) and IL-1beta (0.57 pM-5.7 nM) were also studied. In parallel studies, footpad inflammation was induced in NK1 receptor knock-out (KO) and wild-type (WT) mice, and swelling and NO metabolite levels were measured. RESULTS: In cultured synoviocytes, SP, TNF-alpha and IL-1beta induced significantly increased nitrite concentrations. Consistent with a role for NO in SP-mediated inflammatory reactions, the plasma NO metabolite level in WT mice was significantly increased at 3 days following an injection of 10 mg/ml Mycobacterium tuberculosis, but there was no significant change in NK1 KO mice. These results were paralleled by the changes in footpad swelling in WT mice compared to NK1 KO mice. CONCLUSION: SP, like TNF-alpha and IL-1beta, induces NO in both rheumatoid synoviocytes and experimental models of inflammation. Treatments directed against SP may have important and hitherto unrecognised anti-inflammatory effects.
OBJECTIVE: The inflammatory mediator substance P (SP) acts principally through the neurokinin (NK1) receptor. We assessed the influence of SP on production of NO and its possible role in the pathogenesis of rheumatoid arthritis (RA). METHODS: The effect of SP (0.1-100 nM) on concentrations of the NO metabolite, nitrite, produced by synovial fibroblasts from RA patients was studied. For comparison, the effects of TNF-alpha (0.57 pM-5.7 nM) and IL-1beta (0.57 pM-5.7 nM) were also studied. In parallel studies, footpad inflammation was induced in NK1 receptor knock-out (KO) and wild-type (WT) mice, and swelling and NO metabolite levels were measured. RESULTS: In cultured synoviocytes, SP, TNF-alpha and IL-1beta induced significantly increased nitrite concentrations. Consistent with a role for NO in SP-mediated inflammatory reactions, the plasma NO metabolite level in WT mice was significantly increased at 3 days following an injection of 10 mg/ml Mycobacterium tuberculosis, but there was no significant change in NK1 KO mice. These results were paralleled by the changes in footpad swelling in WT mice compared to NK1 KO mice. CONCLUSION:SP, like TNF-alpha and IL-1beta, induces NO in both rheumatoid synoviocytes and experimental models of inflammation. Treatments directed against SP may have important and hitherto unrecognised anti-inflammatory effects.