title: Substance P C-terminal octapeptide analogues augment tumor necrosis factor-alpha release by human blood monocytes and macrophages.
abstract: We have investigated the effects of the substance P C-terminal octapeptide analogues [Pro4, Glu (OBzl)11] SP4-11, [Hyp4, Glu(OBzl)11] SP4-11, [cHyp4, Glu(OBzl)11] SP4-11 and [kPro4, Glu(OBzl)11] SP4-11 on the constitutive and/or lipopolysaccharide (LPS)-induced expression of tumor necrosis factor (TNF-alpha) in both freshly isolated human blood monocytes (FIBM) and monocyte-derived macrophages (MDM). The cells were treated with substance P and the substance P analogues at various concentrations (10-14 to 10-6 M) in the presence or absence of LPS and culture supernatants were analyzed for TNF-alpha as measured by an enzyme immunosorbent assay (ELISA). Monocytes and macrophages treated with the substance P analogues alone increased TNF-alpha secretion at a magnitude similar to the effect of entire undecapeptide substance P. The stimulatory effects of the substance P analogues on TNF-alpha secretion are inhibited by substance P antagonists, spantide ([D-Arg-1-D-Trp-7-D-Trp-9-Leu-11]-SP) and CP-96,345 (a nonpeptide antagonist of the substance P receptor), indicating that these effects are specific and substance P receptor-mediated. Treatment of monocytes and macrophages with the substance P analogues in combination with LPS, however, showed no synergistic interaction in upregulation of TNF-alpha. These data indicate that the biological effect of substance P on TNF-alpha production by human monocytes and macrophages depends mainly on the sequence of the C-terminal region of the molecule.
authors.affiliation: Joseph Stokes Jr. Research Institute at Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania Medical School, PA 19104, USA.
authors.forename: W Z
authors.initials: WZ
authors.lastname: Ho
authors.forename: G
authors.initials: G
authors.lastname: Stavropoulos
authors.forename: J P
authors.initials: JP
authors.lastname: Lai
authors.forename: B F
authors.initials: BF
authors.lastname: Hu
authors.forename: V
authors.initials: V
authors.lastname: Magafa
authors.forename: S
authors.initials: S
authors.lastname: Anagnostides
authors.forename: S D
authors.initials: SD
authors.lastname: Douglas
mesh_terms: D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D013373:Substance P / Q000031:analogs & derivatives*; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P