title: A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes.
abstract: Substance P (SP), a potent modulator of neuroimmunoregulation, exerts its activity by binding to the neurokinin-1 receptor (NK-1R). The SP-NK-1R interaction is important in inflammation and viral infections, including HIV infection of human immune cells. We recently demonstrated that SP modulates HIV replication and that a non-peptide SP antagonist CP-96,345 inhibits HIV replication in human monocyte-derived macrophages (MDM) by affecting the SP-NK-1R interaction. In order to examine the effect of the SP antagonist on SP mRNA expression, MDM was incubated with or without CP-96,345 in the presence or absence of HIV infection. SP mRNA expression in these cells was then determined by real-time PCR technology. The effect of CP-96,345 on chemokine gene expression was also investigated by using a cDNA array assay. CP-96,345 down-regulated SP mRNA expression and antagonized exogenous SP-enhanced SP expression at the mRNA level, suggesting that SP autocrine regulation was interrupted by CP-96,345. CP-96,345 inhibited HIV replication in MDM, associated with down-regulated SP mRNA expression in comparison to HIV infection controls. In parallel with down-regulated SP and CCR5 mRNA expression, cDNA array assays indicated that CP-96,345 treatment also inhibited IL-8 gene expression, while enhancing expression of fractalkine and monocyte chemotactic protein-3 (MCP-3). Since SP plays an important role in inflammation and viral infections, these studies may have potential applications for therapeutic intervention of inflammation and viral infection of immune cells.
authors.affiliation: Division of Immunologic and Infectious Diseases, Joseph Stokes Jr. Research Institute at the Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Lai
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Yang
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D054410:Chemokine CCL7; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics; D016207:Cytokines; D018076:DNA, Complementary / Q000032:analysis; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006678:HIV / Q000187:drug effects / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010586:Phagocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; C515450:CCL7 protein, human; C515538:CX3CL1 protein, human; D054410:Chemokine CCL7; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D016207:Cytokines; D018076:DNA, Complementary; D016209:Interleukin-8; D008565:Membrane Proteins; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D013373:Substance P; C066892:CP 96345