SUBSTANCE-P AUGMENTS INTERLEUKIN-10 AND TUMOR-NECROSIS-FACTOR-ALPHA RELEASE BY HUMAN CORD-BLOOD MONOCYTES AND MACROPHAGES

We have investigated the effects of SP on the constitutive and/or lipo polysaccharide (LPS)-induced expression of interleukin-10 (IL-10) and tumor necrosis factor (TNF-alpha) in both freshly isolated cord blood monocytes (FICBM) and cord blood monocyte-derived macrophages (CBMDM). The cells were treated with SP at various concentrations (10(-14) to 10(-6) M) in the presence or absence of LPS and culture supernatants w ere analyzed for IL-10 and TNF-alpha as measured by an enzyme immunoso rbent assay (ELISA). FICBM and CBMDM treated with SP alone increased T NF-alpha secretion. The stimulatory effects of SP on TNF-alpha secreti on are inhibited by a anti-SP polyclonal antibody and SP antagonists, spantide ([D-Arg-1-D-Trp-7-D-Trp-9-Leu-11]-SP) and CP-96,345 (a nonpep tide antagonist of the SP receptor). Although the treatment with SP al one did not enhance IL-10 secretion by both freshly isolated and cultu red cord monocytes, treatment with SP in combination with LPS leads to a synergistic interaction in upregulation of IL-10 secretion. Fragmen ts of SP (SP1-4 and SP5-11) in the presence or absence of LPS show lit tle effects on IL-10 secretion by FICBM. SP reverses the inhibitory ef fect of IFN-gamma on LPS-induced IL-10 secretion by FICBM. In addition , the two SP antagonists and the anti SP polyclonal antibody blocked t he SP effect on IL-10 secretion by FICBM, indicating that these effect s are specific and SP receptor mediated, Thus, SP is likely to play an important role in certain inflammatory conditions in the immune and n ervous systems.