Substance P augments interleukin-10 and tumor necrosis factor-α release by human cord blood monocytes and macrophages

Abstract We have investigated the effects of SP on the constitutive and/or lipopolysaccharide (LPS)-induced expression of interleukin-10 (IL-10) and tumor necrosis factor (TNF-α) 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 were analyzed for IL-10 and TNF-α as measured by an enzyme immunosorbent assay (ELISA). FICBM and CBMDM treated with SP alone increased TNF-α secretion. The stimulatory effects of SP on TNF-α secretion 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 nonpeptide antagonist of the SP receptor). Although the treatment with SP alone did not enhance IL-10 secretion by both freshly isolated and cultured cord monocytes, treatment with SP in combination with LPS leads to a synergistic interaction in upregulation of IL-10 secretion. Fragments of SP (SP 1–4 and SP 5–11 ) in the presence or absence of LPS show little effects on IL-10 secretion by FICBM. SP reverses the inhibitory effect of IFN-γ on LPS-induced IL-10 secretion by FICBM. In addition, the two SP antagonists and the anti-SP polyclonal antibody blocked the SP effect on IL-10 secretion by FICBM, indicating that these effects are specific and SP receptor mediated. Thus, SP is likely to play an important role in certain inflammatory conditions in the immune and nervous systems.