β-Funaltrexamine inhibits chemokine (CXCL10) expression in normal human astrocytes

Abstract

Neuroinflammation is an integral component of neurodegenerative disorders, CNS infection and trauma. Astroglial chemokines, such as CXCL10, are instrumental in neuroinflammatory signaling as well as neurotoxicity. We have utilized proinflammatory-induced CXCL10 expression in normal human astrocytes (NHA) as a model in which to assess the anti-inflammatory actions of the selective, mu-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). Interferon (IFN)γ + HIV-1 Tat-induced CXCL10 expression (secreted protein and mRNA) was inhibited by co-treatment with β-FNA. Neither the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH2 (CTAP) nor the nonselective opioid receptor antagonist, naltrexone inhibited IFNγ + HIV-1 Tat-induced CXCL10 expression. Furthermore, co-treatment with excess CTAP or naltrexone did not prevent β-FNA mediated inhibition of IFNγ + HIV-1 Tat-induced CXCL10 expression. Additionally, we utilized an inhibitor of NF-κB activation (SN50) to demonstrate that IFNγ + HIV-1 Tat-induced CXCL10 expression is NF-κB-dependent in NHA. Subsequent experiments revealed that β-FNA did not significantly affect NF-κB activation. Interestingly, we discovered that β-FNA inhibited p38 activation as indicated by decreased expression of phospho-p38. Together, these findings suggest that the inhibitory actions of β-FNA are MOR-independent and mediated, in part, via a transcriptional mechanism. These findings add to our understanding of the mechanism by which chemokine expression is inhibited by β-FNA. In conjunction with future investigations, these novel findings are expected to provide insights into the development of safe and effective treatments for neuroinflammation.

The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice

“…Activation of p38 MAPK occurs following pro-inflammatory stimuli that induce the expression of the chemokine CXCL10 in astrocytes (Davis et al, 2013). Therefore, activated p38 MAPK (phospho-p38) was determined in β-FNA treated and control NHA.…”

“…Based on our published reports, it is clear that β-FNA inhibits inflammatory signaling regardless of the pro-inflammatory stimulus or cell type, as determined using several endpoints (Davis et al, 2007; 2008, 2013; Stevens et al, 2013). Continuing our efforts to identify the mechanism of action for the anti-inflammatory effects of β-FNA, the present study focused on IL-1β-induced signaling in human astrocytes.…”

“…Recently, we performed a series of experiments to further address the potential involvement of opioid receptors, including MOR, kappa opioid receptor (KOR) and nociceptin/orphanin FQ receptor (ORL). β-FNA actions were not blocked by concurrent treatment with selective opioid antagonists targeting their respective opioid receptors (Davis et al, 2013). …”

“…It remains to be determined whether β-FNA prevents nuclear translocation directly or inhibits upstream events in the NF-κB signaling pathway. We recently determined that IFNγ + HIV-1 Tat-induced CXCL10 expression in NHA was also inhibited by β-FNA, but NF-κB activation was not (Davis et al, 2013). It may be that β-FNA effects on NF-κB signaling in astrocytes are, in part, stimulus-dependent.…”

“…Interferon-γ (IFNγ) + HIV-1 Tat-induced CXCL10 expression in NHA also was inhibited by β-FNA (Davis et al, 2013). Importantly, neither the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH 2 (CTAP) nor the nonselective opioid receptor antagonist, naltrexone inhibited IFNγ+HIV-1Tat-induced CXCL10 expression.…”