Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages

Khabbazi, Samira; Goumon, Yannick; Parat, Marie-Odile

doi:10.1038/srep11389

Cited by 56 publications

(42 citation statements)

References 29 publications

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“…IL-4, IL-10, and TGF-β are powerful anti-inflammatory cytokines with a wide spectrum of biological effects [26–28]. Therefore, we tested whether metformin inhibit inflammatory response via regulating anti-inflammatory cytokines production.…”

Section: Discussionmentioning

confidence: 99%

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Pan

Sun

Jiang

et al. 2016

J Neuroinflammation

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BackgroundTolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.MethodsThe microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.ResultsWe found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.ConclusionsMetformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0754-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Pan

Sun

Jiang

et al. 2016

J Neuroinflammation

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“…Recently, another effect of opioids affecting the tumor microenvironement has been unveiled, with the ability of morphine to prevent the polarization of macrophages into an M2, tumor-associated macrophage (TAM)-like phenotype [62]. In this study, macrophages were exposed in vitro to either cancer cells or IL-4 to induce their M2 polarization, and morphine was shown to prevent the expression of both MMP-9 and M2 markers in these models.…”

Section: Indirect Effects Of Opioids On Tumor Biologymentioning

confidence: 96%

Opioid Analgesic Agents and Cancer Cell Biology

Xie

Parat

2015

Curr Anesthesiol Rep

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There is growing interest in the notion that perioperative factors may influence the long-term outcome of cancer surgery. Among these factors, pharmacologic agents including anesthetics and analgesics have been scrutinized for their potential effect on tumors. Opioids are particularly interesting in this context, as conflicting literature reports both pro-and anti-tumor effects for this class of drugs in every aspect of tumor growth and metastasis that has been examined. Cancer and non-cancer cells important to the tumor biology may be affected, as demonstrated using a variety of in vitro and preclinical models. More evidence is required to optimize the perioperative pain management of cancer surgery patients.

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“…Morphine has been tested for its effect on cancer cells, immune cells and endothelial cells grown individually (reviewed in Afsharimani et al, 2011; Xie and Parat, 2015). Furthermore, we have unveiled the ability of morphine to modulate the interaction between cancer and non-cancer cells important in the tumor microenvironment, including endothelial cells and macrophages (Afsharimani et al, 2014; Khabbazi et al, 2015, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…We have previously demonstrated the ability of morphine to prevent macrophage M2 polarization elicited by tumor cells (Khabbazi et al, 2015). In the current study, we hypothesized that the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G), which is documented to be active at TLR4 (Hutchinson et al, 2010; Stevens et al, 2013), would modulate the M1 polarization of macrophages in vitro .…”

Section: Introductionmentioning

confidence: 99%

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

Khabbazi

Xie

et al. 2016

Front. Pharmacol.

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Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-γ). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-α in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-α, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages.

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Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages

Cited by 56 publications

References 29 publications

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Opioid Analgesic Agents and Cancer Cell Biology

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

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