A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes

J Neuroimmunol. 2002 Jul;128(1-2):101-8. doi: 10.1016/s0165-5728(02)00164-9.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Autocrine Communication / drug effects
  • Autocrine Communication / genetics
  • Biphenyl Compounds / pharmacology*
  • Cells, Cultured
  • Chemokine CCL7
  • Chemokine CX3CL1
  • Chemokines, CX3C / genetics
  • Cytokines*
  • DNA, Complementary / analysis
  • Down-Regulation / drug effects*
  • Down-Regulation / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • HIV / drug effects
  • HIV / immunology
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • Humans
  • Interleukin-8 / genetics
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Membrane Proteins / genetics
  • Monocyte Chemoattractant Proteins / genetics
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / immunology
  • Oligonucleotide Array Sequence Analysis
  • Phagocytes / drug effects*
  • Phagocytes / immunology
  • Phagocytes / virology
  • RNA, Messenger / metabolism
  • Receptors, Neurokinin-1 / drug effects
  • Receptors, Neurokinin-1 / immunology
  • Receptors, Neurokinin-1 / metabolism
  • Substance P / antagonists & inhibitors
  • Substance P / genetics*
  • Virus Replication / drug effects
  • Virus Replication / immunology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Biphenyl Compounds
  • CCL7 protein, human
  • CX3CL1 protein, human
  • Chemokine CCL7
  • Chemokine CX3CL1
  • Chemokines, CX3C
  • Cytokines
  • DNA, Complementary
  • Interleukin-8
  • Membrane Proteins
  • Monocyte Chemoattractant Proteins
  • RNA, Messenger
  • Receptors, Neurokinin-1
  • Substance P
  • CP 96345