Orphanin FQ/Nociceptin Activates Nuclear Factor Kappa B

Journal of Neuroimmune Pharmacology - Tập 6 - Trang 617-625 - 2011
Courtney L. Donica1,2, Vanessa I. Ramirez1, Hibah O. Awwad1, Nurulain T. Zaveri3, Lawrence Toll4, Kelly M. Standifer1,2,5,6
1Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, USA
2Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, USA
3Astraea Therapeutics, LLC, Mountain View, USA
4SRI International, Menlo Park, USA
5Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
6University of Oklahoma College of Pharmacy, Oklahoma City, USA

Tóm tắt

Endogenous neuropeptide orphanin FQ/nociceptin (OFQ/N) and its receptor, nociceptin orphanin FQ peptide receptor (NOPr), play a modulatory role throughout the body including nociceptive sensitivity, motor function, spatial learning, and the immune system. NOPr is an inhibitory G protein coupled receptor (GPCR) that modulates expression and release of inflammatory mediators from immune cells and in the CNS. Inhibitory GPCRs have been shown to activate the immune and central nervous system regulator, nuclear factor kappa B (NFκB), whose family consists of several subunits. When activated, NFκB translocates to the nucleus and can modify transcription. To determine if OFQ/N modulates NFκB activity, SH-SY5Y human neuroblastoma cells were treated with OFQ/N and assessed for changes in nuclear accumulation, DNA binding, and transcriptional activation. For the first time, we show that OFQ/N increases the nuclear accumulation (1.9–2.8-fold) and the DNA binding of NFκB (2.9-fold) by 2 h as determined by immunoblotting and electromobility shift assay, respectively. OFQ/N induction of NFκB binding to DNA is protein kinase C-dependent and NOPr-specific. OFQ/N stimulated binding of both NFκB p50 and p65 subunits to their consensus binding site on DNA. OFQ/N also induces transcriptional activation of an NFκB reporter gene 2.2-fold by 2 h with an EC50 of 6.3 nM. This activation of NFκB by OFQ/N suggests a likely mechanism for its modulation of the central nervous and immune systems.

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