PRODUCTION OF INTERLEUKIN-1 BY MICROGLIA IN RESPONSE TO SUBSTANCE-P - ROLE FOR A NONCLASSICAL NK-1 RECEPTOR

Substance P (SP) is a central and peripheral neurotransmitter which has been found in multiple sclerosis plaques. SP stimulates peripheral immune cells and may play a role in some chronic inflammatory diseases. Human peripheral monocyte/macrophages have been shown to produce the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha) in response to SP. Therefore, in this study we examined rat brain microglia for the presence of SP receptors and production of IL-1 and TNFalpha in response to SP. Microglia had 4900 +/- 950 (mean +/- SE) receptors per cell fitting a two-site model. Four percent of these were high-affinity receptors with a K(d) of 8.2 x 10(-8) M +/- 3.6 x 10(-8) M (mean +/- SE), and 96% of them were low-affinity receptors with a K(d) of 2.1 X 10(-6) M +/- 5.2 x 10(-7)M (mean +/- SE). Competitive studies with CP 96,345 and other SP analogs demonstrate these to be non-classical NK-1 receptors. SP alone did not stimulate IL-1 or TNFalpha production. However, SP in synergy with lipopolysaccharide (LPS) quadrupled IL-1 production compared to LPS alone, but did not affect TNFalpha production. These results have implications for certain inflammatory conditions in the central nervous system.