title: 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.
authors: Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, United States. randall.davis@okstate.edu
authors: Randall L
authors: RL
authors: Davis
authors: Subhas
authors: S
authors: Das
authors: Daniel J
authors: DJ
authors: Buck
authors: Craig W
authors: CW
authors: Stevens
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D017931:DNA Primers; D004789:Enzyme Activation; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D017931:DNA Primers; D015696:Gene Products, tat; D016328:NF-kappa B; D009271:Naltrexone; C024524:beta-funaltrexamine; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases
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