bims-stacyt Biomed news on
Starvation pathways leading to cytokine regulation
Issue of 2018‒03‒25
nine papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Cell Metab. 2018 Mar 01. doi: 10.1016/j.cmet.2018.02.009
    Abstract:  Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.
    Keywords:  ER stress; IRE1α; RIG1; UPR; anti-tumor immunity; cancer; diet; dietary restriction; immunosurveillance
  2. Cell Physiol Biochem. 2018 Mar 10. doi: 10.1159/00048816645(6):
    Abstract:  BACKGROUND/AIMS: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11's role in NSCLC and the detailed mechanism behind it. METHODS: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial-mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. RESULTS: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial-mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. CONCLUSIONS: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.
    Keywords:  EMT; Hypoxia; IL-11; NSCLC
  3. Biomed Pharmacother. 2018 Mar 15. doi: 10.1016/j.biopha.2018.03.048102
    Abstract:  Glycine modulates inflammatory processes mediated by macrophages and adipocytes through decreasing the secretion of TNF-α, IL-6, and leptin, while increasing adiponectin. These effects have been associated with the inactivation of NF-κB in response to TNF-α, across an increase of its inhibitor IκB-α in adipocytes. However, glycine upstream mainly influences the IκB kinase (IKK) complex, a multi-protein kinase complex considered a critical point in regulation of the NF-κB pathway; whether that is responsible for the TNF-α-induced phosphorylation of IkB has not been explored. Additionally, although previous studies have described glycine interactions with specific receptors (GlyR) in different immune system cell types, it is currently unknown whether adipocytes present GlyR. In this research, participation of the IKK-α/β complex in the inhibition of the TNF-α/NF-κB pathway by glycine was evaluated and associated with the synthesis and secretion of inflammatory cytokines in 3T3-L1 adipocytes. Furthermore, we also explored GlyR expression, its localization on the plasmatic membrane, intracellular calcium concentrations [Ca2+]i and strychnine antagonist action over the GlyR in these cells. Glycine decreased the IKK-α/β complex and the phosphorylation of NF-κB, diminishing the expression and secretion of IL-6 and TNF-α, but increasing that of adiponectin. GlyR expression and its fluorescence in the plasma membrane were increased in the presence of glycine. In addition, glycine decreased [Ca2+]i; whereas strychnine + glycine treatment inhibited the activation of NF-κB observed with glycine. In conclusion, the reduction of TNF-α and IL-6 and suppression of the TNF-α/NF-κB pathway by glycine may be explained in part by inhibition of the IKK-α/β complex, with a possible participation of GlyR in 3T3-L1 adipocytes.
    Keywords:  Adipocytes; Glycine; Glycine receptors; IKK-α/β complex; Inflammatory cytokines; TNF-α/NF-κB
  4. Cell Physiol Biochem. 2018 Mar 10. doi: 10.1159/00048817045(6):
    Abstract:  BACKGROUND/AIMS: Lipopolysaccharide (LPS) pretreatment has a strong neuroprotective effect on cerebral ischaemia/reperfusion injury (IRI), but the mechanism has not been fully elucidated to date. This study investigated the effect of LPS pretreatment on the pathway mediated by endoplasmic reticulum (ER) stress-CCAAT/enhancer-binding protein- homologous protein (CHOP) and the role of this pathway on cerebral ischaemia/reperfusion (I/R)-induced inflammation and apoptosis. METHODS: Healthy male BALB/c mice were randomised into four groups as follows: sham operation group (sham group, n=30); LPS group (BALB/c mice treated with LPS, n=30); ischaemia/reperfusion group (I/R group, n=30) and I/R+LPS group (BALB/c mice treated with LPS before ischaemia, n=30). The mice were pre-treated with LPS (0.2 mg/kg) intra-peritoneally for three days prior to cerebral ischaemia. After 24 hours, the neurological deficit score, TTC staining and TUNEL assay were used to assess the neuroprotective effect of the LPS pretreatment against cerebral IRI. To assess whether the ER stress-CHOP pathway participated in the LPS-pretreatment neuroprotective mechanism, the expression levels of related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the ischaemic cortical penumbra were detected via a western blot analysis. An immunohistochemical study was used to detect the expression and location of CHOP in the cortical penumbra. To further assess the protective effect of the LPS pretreatment, the concentrations of inflammatory factors (TNF-α, IL-6, IL-1β and IL-10) in the cortical penumbra were measured by ELISA, and ER stress-CHOP pathway inflammation-related caspase-11 was analysed through western blot analysis. RESULTS: As demonstrated by the experiments, the pretreatment with LPS significantly reduced the neurological deficit score and the infarct size of cerebral IRI. The expression levels of ER stress-CHOP pathway related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the cortical penumbra were significantly decreased by LPS, as well as the level of apoptosis in the cells in the brain. Immunohistochemistry showed that the expression of CHOP significantly decreased after the LPS pretreatment. Furthermore, the concentrations of inflammatory factors (TNF-α, IL-1β, IL-6) were reduced after the LPS pretreatment, whereas the anti-inflammatory cytokine IL-10 was upregulated. In addition, ER stress-CHOP pathway inflammation-related caspase-11 expression was significantly suppressed after the pretreatment with LPS. CONCLUSIONS: LPS pretreatment significantly ameliorates the effects of cerebral IRI by inhibiting inflammation and apoptosis, and the potential mechanism of the neuroprotective effect may be associated with the ER stress-CHOP mediated signalling pathway.
    Keywords:  Apoptosis; Cerebral ischaemia/reperfusion injury; Inflammation; Lps pretreatment
  5. Cell Physiol Biochem. 2018 Mar 10. doi: 10.1159/00048816545(6):
    Abstract:  BACKGROUND/AIMS: The role of Rictor in hepatic ischemia/reperfusion (I/R) injury remains unknown. Here, we comprehensively examined the role of Rictor in hepatic I/R injury. METHODS: We studied the expression of Rictor during hepatic I/R injury. The regulatory effects of Rictor on inflammatory responses, cytokine and chemokine release, apoptotic and anti-apoptotic responses, and autophagy induction during hepatic I/R injury were identified via the shRNA-mediated knockdown of Rictor. Subsequently, we collected the liver and blood samples of these mice to evaluate liver injury, mRNA and protein levels. Additionally, the signaling pathways induced by Rictor were investigated. Furthermore, the extent of activation of MAPKs in response to Rictor deficiency was investigated in lipopolysaccharide (LPS)-treated RAW264.7 cells. The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression of Rictor was increased during hepatic I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Rictor deficiency enhanced the extent of liver injury by increasing macrophage and neutrophil infiltration, promoting cytokine and chemokine release, aggravating hepatocyte apoptosis, suppressing anti-apoptotic responses, and inhibiting autophagy induction during both hepatic I/R and H/R injury. Rictor was associated with the activation of hepatic I/R injury-induced MAPK signaling. In addition, Rictor deficiency affected MAPK activation in LPS-treated RAW264.7 cells. CONCLUSION: Rictor can substantially ameliorate I/R-induced liver injury. Therefore, our findings strongly suggest a therapeutic value of the Rictor/mTORC2 axis in hepatic I/R injury.
    Keywords:  Autophagy; Hepatic ischemia/reperfusion injury; MTORC2; Rictor
  6. Biochem Pharmacol. 2018 Mar 15. doi: 10.1016/j.bcp.2018.03.013
    Abstract:  Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of Sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.
    Keywords:  Autophagy; Canagliflozin; Diabetes; Inflammation; SGLT2; p62
  7. Clin Exp Med. 2018 Mar 17. doi: 10.1007/s10238-018-0495-4
    Abstract:  Altered mitochondrial DNA (mtDNA) is the most common denominator to numerous metabolic diseases. The present study sought to investigate the correlation between mtDNA content in lymphocytes and associated clinical risk factors for impaired fasting glucose (IFG). We included 23 healthy control and 42 IFG participants in this cross-sectional study. The measurements of mtDNA content in lymphocytes and pro-inflammatory markers derived from both normal and diseased individuals were quantified. Spearman partial correlation and multivariate statistical analyses were employed to evaluate the association between mtDNA content and other metabolic covariates in IFG. Reduced mtDNA content was observed in the IFG group with microvascular complications than those without complications. The IFG patients with lowest median of mtDNA content had considerably elevated hyperglycemia, insulin resistance and inflammation. The adjusted partial correlation analysis showed that mtDNA content was positively correlated with HDL-cholesterol and IL-10 (P < 0.005 for all). Further, multiple linear regression analyses verified that reduced mtDNA content in lymphocytes was independently associated with HOMA-IR (β = 0.027, P = 0.003), HbA1c (β = 0.652, P = 0.002), HDL-cholesterol (β = - 1.056, P = 0.021), IL-6 (β = 0.423, P = 0.002), IL-10 (β = - 1.234, P = 0.043) and TNF-α (β = 0.542, P < 0.001) after adjustment for confounding factors. Our data show that reduced mtDNA content in lymphocytes was associated with insulin resistance and inflammation in individuals with IFG.
    Keywords:  Impaired fasting glucose; Inflammation; Insulin resistance; Lymphocytes; mtDNA
  8. Redox Biol. 2018 Mar 09. doi: 10.1016/j.redox.2018.03.00216
    Abstract:  Stroke is the leading cause of adult disability and mortality in most developing and developed countries. The current best practices for patients with acute ischemic stroke include intravenous tissue plasminogen activator and endovascular thrombectomy for large-vessel occlusion to improve clinical outcomes. However, only a limited portion of patients receive thrombolytic therapy or endovascular treatment because the therapeutic time window after ischemic stroke is narrow. To address the current shortage of stroke management approaches, it is critical to identify new potential therapeutic targets. The mitochondrion is an often overlooked target for the clinical treatment of stroke. Early studies of mitochondria focused on their bioenergetic role; however, these organelles are now known to be important in a wide range of cellular functions and signaling events. This review aims to summarize the current knowledge on the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation and scavenging, electron transport chain dysfunction, apoptosis, mitochondrial dynamics and biogenesis, and inflammation. A better understanding of the roles of mitochondria in ischemia-related neuronal death and protection may provide a rationale for the development of innovative therapeutic regimens for ischemic stroke and other stroke syndromes.
    Keywords:  Apoptosis; Inflammation; Ischemic stroke; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy
  9. Biochem Biophys Res Commun. 2018 Apr 15. doi: 10.1016/j.bbrc.2018.03.110498(4):
    Abstract:  Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis. As LPS concentration increasing, phagocytosis activity of KCs decreased; but releasing of TNF-α and IL-6 increased. After treatment with KCCM, mRNA level of SOCS3, JAK2 and STAT3 as well as protein expression of SOCS3, p-JAK2 and p-STAT3 in steatosis BRL-3A cells increased significantly, which were inhibited by AG490 or ROZ treatment. Taken together, these results indicated that KCCM attributed to KCs dysfunction facilitated hepatocyte steatosis through promoting expressing SOCS3; but PPARγ agonist ROZ alleviated steatosis through reducing SOCS3 expression by inhibiting JAK2/STAT3 in hepatocytes.
    Keywords:  Hepatocyte steatosis; JAK2; PPARγ; SOCS3; STAT3