Production of interleukin-1 by microglia in response to substance P: role for a non-classical 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 (TNF alpha) 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 TNF alpha 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 Kd 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 Kd 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 TNF alpha production. However, SP in synergy with lipopolysaccharide (LPS) quadrupled IL-1 production compared to LPS alone, but did not affect TNF alpha production. These results have implications for certain inflammatory conditions in the central nervous system.