Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway

Rahiman, Siti Sarah Fazalul; Morgan, Michael; Gray, Paul; Shaw, P. Nicholas; Cabot, Peter J.

doi:10.1016/j.peptides.2017.02.004

Cited by 14 publications

(9 citation statements)

References 50 publications

(47 reference statements)

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“…Opioid Receptor Agonists Bind to TLR4 and Non-stereoselectively Activate TLR4 Many clinically relevant opioid receptor agonists, such as morphine, fentanyl, and oxycodone, bind to TLR4 by docking to the LPS-binding pocket of myeloid differentiation (MD)-2 (9,21,25,26). Additionally, endogenous opioid peptides, for example, endomorphin (MOR), enkephalin (DOR), and dynorphin (KOR), and certain opioid metabolites are also TLR4 ligands (27)(28)(29). Morphine-3-glucuronide (M3G), an inactive metabolite of morphine, has little to no affinity for opioid receptors but enhances pain by activating the TLR4 signaling pathway (29).…”

Section: Tlr4/opioid Receptor Pathway Crosstalkmentioning

confidence: 99%

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

et al. 2020

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Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-...

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Section: Tlr4/opioid Receptor Pathway Crosstalkmentioning

confidence: 99%

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

et al. 2020

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confidence: 99%

“…Dynorphins produced during inflammatory conditions display anti-inflammatory effects by attenuating translocation of nuclear factor-KB and consequently production of tumour necrosis factorα and IL-1β (Rahiman et al, 2017). Inhibition of nuclear-factor KB is likely a major mechanism explaining the anti-inflammatory effects of opioids (Rahiman et al, 2017). Also, activation of KOR by dynorphins negatively regulates many immune cell functions including cytokine production by macrophages (Alicea et al, 1996), T cell proliferation (Guan et al, 1997), phagocytoses (Szabo et al, 1993) and antibody production (Morgan, 1996).…”

mentioning

confidence: 99%

In major depression, increased kappa and mu opioid receptor levels are associated with immune activation

Al‐Hakeim

Al-Fadhel

Al-Dujaili

et al. 2020

Acta Neuropsychiatr.

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Objective:This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin – mu opioid receptor (MOR) and immune-inflammatory system.Methods:The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males.Results:Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence.Conclusion:Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

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“…Both the cell lines were differentiated according to the differentiation protocol to form myotubes. The HCS was performed according to the protocol described by Rahiman et al (2017) and Proszynski et al (2009) with some modifications. Cells were fixed by Image-iTTM Fixative Solution (High purity 4% formaldehyde in PBS, methanol-free) according to the manufacturer's protocol using 15 µL of Image-iTTM Fixative Solution for 10-15 min at room temperature followed by washing with PBS.…”

Section: High Content Screening (Hcs)mentioning

confidence: 99%

Cardioprotective Effects of Arjunolic Acid in LPS-Stimulated H9C2 and C2C12 Myotubes via My88-Dependent TLR4 Signaling Pathway

Hasan¹,

Madhavan²,

Noruddin³

et al. 2022

Preprint

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Arjunolic acid (AA) is a triterpenoid saponin majorly found in the Terminalia arjuna and is claimed to exert the cardiovascular protective effects as a phytomedicine. However, it is unclear how AA exerts the effects at the molecular level. Hence, this study used an in vitro model using lipopolysaccharide (LPS)-stimulated H9C2 and C2C12 myotubes to investigate the cardioprotective effects of arjunolic acid (AA) via MyD88-dependant TLR4 downstream signaling markers expression. The myotubes were developed by differentiating rat H9C2 and mouse C2C12 myoblast cells. The MTT viability assay was used to assess the cytotoxicity of AA. LPS induced in vitro cardiovascular disease model was developed in H9C2 and C2C12 myotubes. The treatment groups were designed such as control (untreated), LPS control, positive control (LPS+ pyrrolidine dithiocarbamate (PDTC)-25 µM), and treatment groups were co-treated with LPS and three doses of AA (50, 75, and 100 µM). The changes in the expression of TLR4 downstream signaling markers were evaluated through High Content Screening (HCS) and Western Blot (WB) analysis. The outcomes demonstrated that the expression of MyD88, MAPK, JNK, and NFκB markers were significantly upregulated in the LPS-treated groups compared to the untreated control. Evidently, the HCS analysis revealed that MyD88, NF-κB, p38, and JNK were significantly downregulated in the H9C2 myotube in the AA treated groups (50, 75, and 100 µM). For, the C2C12 myotube, the expression of NFκB was downregulated. TLR4 marker expression in H9C2 and C2C12 myotubes was subsequently decreased by AA treatment, suggesting possible cardioprotective effects of AA.

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Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway

Cited by 14 publications

References 50 publications

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

In major depression, increased kappa and mu opioid receptor levels are associated with immune activation

Cardioprotective Effects of Arjunolic Acid in LPS-Stimulated H9C2 and C2C12 Myotubes via My88-Dependent TLR4 Signaling Pathway

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