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
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Autocrine Communication / drug effects
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Autocrine Communication / genetics
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Biphenyl Compounds / pharmacology*
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Cells, Cultured
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Chemokine CCL7
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Chemokine CX3CL1
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Chemokines, CX3C / genetics
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Cytokines*
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DNA, Complementary / analysis
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Down-Regulation / drug effects*
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Down-Regulation / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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HIV / drug effects
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HIV / immunology
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HIV Infections / drug therapy*
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HIV Infections / immunology
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HIV Infections / virology
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Humans
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Interleukin-8 / genetics
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / virology
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Membrane Proteins / genetics
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Monocyte Chemoattractant Proteins / genetics
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Neuroimmunomodulation / drug effects
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Neuroimmunomodulation / immunology
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Oligonucleotide Array Sequence Analysis
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Phagocytes / drug effects*
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Phagocytes / immunology
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Phagocytes / virology
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RNA, Messenger / metabolism
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Receptors, Neurokinin-1 / drug effects
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Receptors, Neurokinin-1 / immunology
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Receptors, Neurokinin-1 / metabolism
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Substance P / antagonists & inhibitors
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Substance P / genetics*
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Virus Replication / drug effects
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Virus Replication / immunology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Biphenyl Compounds
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CCL7 protein, human
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CX3CL1 protein, human
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Chemokine CCL7
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Chemokine CX3CL1
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Chemokines, CX3C
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Cytokines
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DNA, Complementary
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Interleukin-8
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Membrane Proteins
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Monocyte Chemoattractant Proteins
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RNA, Messenger
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Receptors, Neurokinin-1
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Substance P
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CP 96345