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.
Highlights
Dynorphin 1–17 (DYN 1–17) opioid peptide is endogenously released from immunocytes and neurons upon enzymatic cleavage of the precursor prodynorphin molecule, yielding a 17-amino acid sequence
We examine the immunomodulatory effects of DYN 1–17 and major N-terminal fragments observed in the inflammatory environment, on LPS-stimulated NF-κB/p65 nuclear translocation and downstream release of DYN 1-17, NF-kappa B, Interleukin-1beta and TNF-alpha inflammatory cytokines (IL-1β and TNF-α) in THP-1 cells and elucidate the involvement of the kappa-opioid peptide (KOP) receptor in this pathway
Upon adding DYN 1–17 and the N-terminal fragments (DYN 1–6, 1–7, 1–9, 1–10, 1–11), NF-κB/p65 nuclear translocation was significantly inhibited between 20–40% at both high and low concentrations (1 μM and 10 nM, respectively) when compared to the LPS positive control group (p 0.05)
Summary
Dynorphin 1–17 (DYN 1–17) opioid peptide is endogenously released from immunocytes and neurons upon enzymatic cleavage of the precursor prodynorphin molecule, yielding a 17-amino acid sequence. To other endogenous opioids, DYN 1–17 is susceptible to rapid enzymatic degradation, generating a variety of smaller fragments representing a number of cleavage points [4]. Our laboratory has previously demonstrated that DYN 1–17 is biotransformed in rat inflamed tissue to a unique array of opioid and non-opioid fragments, different to those seen within non-inflamed tissue or blood at acidic pH, reflecting the naturally occurring inflammatory environment [5]. The underlying signal transduction mechanisms required for these activities, remain poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
