Morphine Modulates NFκB Activation in Macrophages

Roy, Sabita; Cain, Kelly; Chapin, Rebecca B.; Charboneau, Richard; Barke, Roderick A.

doi:10.1006/bbrc.1998.8415

Cited by 150 publications

(123 citation statements)

References 18 publications

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“…We had previously shown that chronic morphine treatment results in inhibition of binding of NF-B to its consensus DNA oligonucleotide in macrophages (47). In the current study, we show a similar decrease in NF-B binding to the IFN-␥ promoter element in primary activated murine T cells.…”

Section: Fig 6 Effect Of Morphine Treatment On C-fos and C-jun Mrnasupporting

confidence: 85%

Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways

Wang

Barke

Charboneau

et al. 2003

Journal of Biological Chemistry

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To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-␥ (IFN-␥) promoter in activated T cells from wild type and -opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-␥ 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-␥ 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-␥ promoter activity. The transcription factor activator protein-1, NF-B, and nuclear factor of activated T cells (NFAT) were negatively regulated by morphine. Overexpression of NF-B p65 rescued the inhibitory effect of morphine on IFN-␥ promoter activity. However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-␥ promoter counteracted. The inhibitory effects of morphine were not observed in T cells obtained from -opioid receptor knockout mice, suggesting that morphine modulation of IFN-␥ promoter activity is mediated through the -opioid receptor. In summary, our data indicate that morphine modulation of IFN-␥ promoter activity is mediated through two distinct cAMP-dependent pathways, the NF-B signaling pathway and the ERK1/2, p38 MAPK, AP-1/NFAT pathway.Chronic opioid abusers have been known to experience higher incidence of infectious diseases. It is now well established that opioid use and abuse promotes human immunodeficiency virus infection and disease progression (1, 2). IFN-␥ 1 is a cytokine that modulates all phases of immune processes. It is produced predominantly in activated T cells and large granular lymphocytes as well as natural killer cells (3). IFN-␥ plays a central role in host resistance to infection, notably viral infection (4). Previous studies, including our own, have shown that morphine use and abuse results in the inhibition of IFN-␥ production and may explain why a higher incidence of human immunodeficiency virus and other viral infections is observed in the drug abuse population (5-8). Although morphine's inhibitory effects on IFN-␥ production are well known, the mechanisms by which morphine causes this suppressive effect have not been fully elucidated. In neuronal cells, morphine binds to a G protein-coupled -opioid receptor to induce analgesia (9, 10). Activation of the -opioid receptor leads to regulation of several intracellular effectors, such as modulation of adenylyl cyclase activity (11). Cyclic AMP (cAMP) is a negative regulator of T cell activation. Increased intracellular cAMP conc...

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Section: Fig 6 Effect Of Morphine Treatment On C-fos and C-jun Mrnasupporting

confidence: 85%

Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways

Wang

Barke

Charboneau

et al. 2003

Journal of Biological Chemistry

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“…Notably, however, we also identified regional-specificity in Il6 methylation levels, and therefore the difference in measured methylation levels may represent alterations in cell composition, such as increased microglial infiltration. As IL-1 and TNF- are also secreted by activated macrophages in response to morphine 48 , but were not differentially methylated in the pons, it is unclear how IL-6 alone may be implicated in response to morphine.…”

Section: Discussionmentioning

confidence: 99%

The effect of morphine upon DNA methylation in ten regions of the rat brain

Barrow

Byun

et al. 2017

Epigenetics

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A and Guo, L (2017) The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics, 12 (12 AbstractMorphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1 and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2 and Mtco3), and measured global 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all p<0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all p<0.05). Global 5-mc levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5-hmc levels in the cerebral cortex, hippocampus and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence.

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“…For instance, morphine has been shown to modulate the expression of other cellular proteins that may induce CCR5 expression. Specifically, morphine reportedly modulates the cellular activation of NFB and TNF-␣ in macrophages (27) and interleukin-2 in lymphocytes (28); activation of NFB, TNF-␣, and interleukin-2 has been found to up-regulate CCR5 expression (10,29). Alternatively, morphine may up-regulate CCR5 by inhibiting chemokine synthesis and thus chemotaxis.…”

Section: Infection Of Cem X174 Cells With Sivmac239 or Srv-methodsmentioning

confidence: 99%

Morphine Induces Gene Expression of CCR5 in Human CEM x174 Lymphocytes

Miyagi¹,

Chuang²,

Doi³

et al. 2000

Journal of Biological Chemistry

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All HIV-1 strains studied to date use CCR5, CXCR4, or both receptors to enter cells. Simian immunodeficiency virus (SIV) infection of non-human primates has served as a useful model for understanding AIDS pathogenesis in humans. Research on several genetically divergent SIV isolates has revealed that SIV uses CCR5, and not CXCR4, for entry. CEM x174, a human lymphoid cell line, has been routinely used to cultivate and maintain various SIV strains. However, questions have arisen about how CEM x174, which reportedly was unable to express detectable amounts of CCR5 transcripts, efficiently supports the growth of SIV. In searching for an answer, we resorted to a sensitive competitive reverse transcriptase-polymerase chain reaction procedure in an attempt to detect as well as quantify the amount of CCR5 expression. Here we present our findings, which indicate that CEM x174 indeed expresses CCR5 and that the amount of CCR5 is increased in cells pretreated with morphine. These results correlate well with our previous observations that morphine treatment causes CEM x174 cells to be more susceptible to SIV infection. Similar morphine effect was not observed on CEM x174 cells infected with simian retroviruses, which do not depend on CCR5 for entry. These findings suggest a plausible mechanism whereby opiate drug users render themselves more susceptible to HIV infection, thereby explaining the vast prevalence of HIV infection among endemic drug use populations.

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Morphine Modulates NFκB Activation in Macrophages

Cited by 150 publications

References 18 publications

Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways

Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways

The effect of morphine upon DNA methylation in ten regions of the rat brain

Morphine Induces Gene Expression of CCR5 in Human CEM x174 Lymphocytes

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