Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways
| Autor: | Horace H. Loh, Richard Charboneau, Jinghua Wang, Roderick A. Barke, Sabita Roy |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
T-Lymphocytes Cyclic AMP-Dependent Protein Kinase Type II Pharmacology Biology Lymphocyte Activation Pertussis toxin p38 Mitogen-Activated Protein Kinases Biochemistry Interferon-gamma Mice chemistry.chemical_compound CD28 Antigens Internal medicine Cyclic AMP medicine Animals Promoter Regions Genetic Receptor Molecular Biology Transcription factor Mice Inbred BALB C Forskolin Morphine NFATC Transcription Factors Activator (genetics) Kinase NF-kappa B Nuclear Proteins NFAT Cell Biology Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins Transcription Factor AP-1 Endocrinology chemistry Mitogen-Activated Protein Kinases Signal transduction Proto-Oncogene Proteins c-fos Signal Transduction Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 278:37622-37631 |
| ISSN: | 0021-9258 |
| Popis: | To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-gamma (IFN-gamma) promoter in activated T cells from wild type and mu-opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-gamma promoter activity in a dose-dependent manner. Chronic morphine treatment of T cells increased intracellular cAMP. To evaluate the role of cAMP in morphine's modulatory function, the effects of dibutyryl cyclic AMP and forskolin were investigated. Both dibutyryl cyclic AMP and forskolin treatment inhibited IFN-gamma promoter activity. Treatment with pertussis toxin, but not with a protein kinase A inhibitor, antagonized morphine's inhibitory effects. Morphine inhibited phosphorylation of ERK1/2 and p38 MAPK; in addition, morphine treatment in the presence of either ERK1/2 or p38 MAPK inhibitor (PD98059 or SB203580) resulted in an additive inhibition of IFN-gamma promoter activity. The transcription factor activator protein-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) were negatively regulated by morphine. Overexpression of NF-kappaB p65 rescued the inhibitory effect of morphine on IFN-gamma promoter activity. However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-gamma promoter counteracted. The inhibitory effects of morphine were not observed in T cells obtained from mu-opioid receptor knockout mice, suggesting that morphine modulation of IFN-gamma promoter activity is mediated through the mu-opioid receptor. In summary, our data indicate that morphine modulation of IFN-gamma promoter activity is mediated through two distinct cAMP-dependent pathways, the NF-kappaB signaling pathway and the ERK1/2, p38 MAPK, AP-1/NFAT pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|