A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes.
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.
Lai
Jian-Ping
JP
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.
Ho
Wen-Zhe
WZ
Yang
Ji-Hong
JH
Wang
Xu
X
Song
Li
L
Douglas
Steven D
SD
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
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