Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway |
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| Institution: | 1. School of Pharmacy, The University of Queensland, Woolloongabba 4102, QLD, Australia;2. School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia;3. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, QLD, Australia;4. School of Medicine, The University of Queensland, Herston 4006, QLD, Australia;5. Department of Anaesthesia, Princess Alexandra Hospital, Woolloongabba 4102, QLD, Australia;1. Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait;2. The Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA;1. Max-Planck-Institute for Metabolism Research, Gleueler Strasse 50a, 50931 Köln, Germany;2. Cologne Excellence Cluster on Cellular Stress Responses in Ageing Associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Köln, Germany;3. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital, Joseph-Stelzmann-Strasse 26, 50931 Köln, Germany;3. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605;5. Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, 75724 Paris Cedex 15, France;4. Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro, Brazil;6. Center of Chronic Immunodeficiency and Center of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, 79106 Freiburg im Breisgau, Germany;1. Department of Respiratory Medicine, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China;2. Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, Guangxi, China;3. Guangxi Colleges and Universities Key Laboratory of Respiratory Disease, Guilin 541001, Guangxi, China;4. Department of Respiratory Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421000, Hunan, China |
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| Abstract: | Dynorphin 1-17 (DYN 1-17) is biotransformed rapidly to a range of fragments in rodent inflamed tissue with dynorphin 3-14 (DYN 3-14) being the most stable and prevalent. DYN 1-17 has been shown previously to be involved in the regulation of inflammatory response following tissue injury, in which the biotransformation fragments of DYN 1-17 may possess similar features. This study investigated the effects of DYN 3-14 on lipopolysaccharide (LPS)-induced nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of pro-inflammatory cytokines interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in differentiated THP-1 cells. Treatment with DYN 3-14 (10 nM) resulted in 35% inhibition of the LPS-induced nuclear translocation of NF-κB/p65. Furthermore, DYN 3-14 modulated both IL-1β and TNF-α release; inhibiting IL-1β and paradoxically augmenting TNF-α release in a concentration-independent manner. A number of opioids have been implicated in the modulation of the toll-like receptor 4 (TLR4), highlighting the complexity of their immunomodulatory effects. To determine whether DYN 3-14 modulates TLR4, HEK-Blue™−hTLR4 cells were stimulated with LPS in the presence of DYN 3-14. DYN 3-14 (10 μM) inhibited TLR4 activation in a concentration-dependent fashion by suppressing the LPS signals around 300-fold lower than LPS-RS, a potent TLR4 antagonist. These findings indicate that DYN 3-14 is a potential TLR4 antagonist that alters cellular signaling in response to LPS and cytokine release, implicating a role for biotransformed endogenous opioid peptides in immunomodulation. |
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| Keywords: | Dynorphin TLR4 LPS NF-κ B/p65 IL-1β TNF-α |
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