Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • RNA interference assays have shown that the inhibition of AM

    2024-07-09

    RNA interference assays have shown that the inhibition of AMPK expression leads to increases in TNF-α, IL-6 and cyclooxygenase-2 (COX-2) levels after LPS stimulus, whereas the transfection of macrophages with a constitutively active form of AMPKα1 results in decreased LPS-induced TNF-α and IL-6 production as well as the heightened production of IL-10. AMPK acts as a potent counter-regulator of macrophage inflammatory function and promoter of macrophage polarization toward an anti-inflammatory phenotype. Furthermore, anti-inflammatory activity of AMPK in macrophages is associated with reduced IκB degradation, enhanced Akt activity and the inactivation of glycogen synthase kinase 3 β (GSK3-β). It is thought that GSK3-β inhibition allows the cAMP response element binding (CREB) protein to compete for the nuclear coactivator protein CBP (CREB-binding protein) required for NF-κB function, which reduces the expression of pro-inflammatory genes (Sag et al., 2008). Other data indicate that AMPK acts as a negative regulator of toll-like receptor-induced inflammatory function. Carroll et al. (2013) found that macrophages and dendritic MI-773 generated from AMPKα1-deficient mice exhibited heightened inflammatory function and an enhanced capacity for antigen presentation, thereby stimulating Th1 and Th17 responses. In antigen presentation assays, bone marrow-derived dendritic cells and macrophages generated in AMPKα1-deficient mice induced significantly higher T cell-produced IL-17 and interferon (IFN)-γ levels. Moreover, CD40 stimulation in dendritic cells deficient for AMPKα resulted in the increased phosphorylation of extracellular signal-regulated kinases (ERK) 1 and 2, p38 and NF-kB p65 and decreased activation of the anti-inflammatory Akt-GSK3β-CREB pathway. These results suggest that the dysregulation of AMPK could play an important role in the development of autoimmune diseases as the result of increased interactions during initial antigen-presenting cell (APC) events as well as the T cell activation of myeloid cells at inflammation sites.
    Role of AMPK in neuroinflammation Some studies indicate that AMPK activation has a potential therapeutic effect on neuroinflammation of the central nervous system. Meares et al. (2013) demonstrated that AMPK activation blocks IFN-γ-induced gene expression, including CCL2, TNF-α, CXCL10 and inducible nitric oxide synthase (iNOS), in primary astrocytes and microglia through the modulation of signal transducer and activator of transcription 1 (STAT1). Likewise, the deletion of AMPKα1 and AMPKα2 in primary astrocytes enhances STAT1 expression, leading to the production of pro-inflammatory cytokines and chemokines. The authors also found that AMPK signaling in experimental autoimmune encephalomyelitis (EAE) is downregulated in the brain at the onset and peak of the disease, which is correlated with the increased expression of IFN-γ and CCL2 in the central nervous system. These results highlight the interaction between AMPK and STAT1 and provide evidence of how bioenergetics and inflammation are related. Other studies have shown that high levels of AMPK are present in embryonic hippocampal neurons in vivo and in cell cultures. In hippocampal neuron cultures, the AMPK-activating agent AICAR protected neurons against death induced by glucose deprivation, chemical hypoxia and exposure to glutamate and amyloid β-peptide. Suppression of the expression of the AMPK α1 and α2 subunits using antisense oligonucleotides resulted in enhanced neuronal death and abolished the neuroprotective effect of AICAR. Based on these results, AMPK protects neurons against metabolic and excitotoxic glutamate insults related to neurodegenerative conditions (Culmsee et al., 2001). Chen et al. (2014) demonstrated that ENERGI-F704, which is a direct AMPK agonist, exerts inhibitory activity on LPS-induced inflammation. Treatment of LPS-stimulated microglia BV2 with ENERGI-F704 decreased activated nuclear translocation and the protein level of NF-κB and consequently reduced pro-inflammatory mediators, such as IL-6, TNF-α, iNOS and COX-2. Another in vitro study evaluated the anti-inflammatory effects of (+)-catechin in LPS-stimulated microglia, the effects of which were linked to the attenuation of NF-kB activation through AMPK (Syed Hussein et al., 2015). Resveratrol, which is a natural AMPK activator, directly reduces morphine tolerance by inhibiting microglial activation through AMPK signaling (Han et al., 2014). Other studies have also shown that treatment with resveratrol inhibits glial activation as well as suppresses neuroinflammation and cancer pain in a model of tibial bone tumor cells implanted in rats (Song et al., 2015).