title: Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells.
abstract: Dynorphin 1-17, (DYN 1-17) opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP) receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1-17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1-17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from lipopolysaccharide (LPS)-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1-17 and a specific range of fragments, with the greatest reduction observed with DYN 1-7 at a low concentration (10 nM). Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not other DYN 1-17 N-terminal fragments (DYN 1-10 and 1-11) on NF-κB/p65 nuclear translocation. DYN 1-17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1-7 at low concentrations (1 nM and 10 pM). These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1-17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.|School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Penang, Malaysia.
authors.forename: Siti Sarah
authors.initials: SS
authors.lastname: Fazalul Rahiman
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, QLD, Australia.|Department of Anaesthesia, Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Paul Nicholas
authors.initials: PN
authors.lastname: Shaw
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Peter John
authors.initials: PJ
authors.lastname: Cabot
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C498143:RELA protein, human; D017473:Receptors, Opioid, kappa; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004399:Dynorphins