Pathogen-associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)-bearing cells of the innate immune system as well as many epithelial cells. In contrast, damage-associated molecular pattern molecules (DAMPs) are cell-derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. Most PAMPs and DAMPs serve as so-called ‘Signal 0s’ that bind specific receptors [Toll-like receptors, NOD-like receptors, RIG-I-like receptors, AIM2-like receptors, and the receptor for advanced glycation end products (RAGE)] to promote autophagy. Autophagy, a conserved lysosomal degradation pathway, is a cell survival mechanism invoked in response to environmental and cellular stress. Autophagy is inferred to have been present in the last common eukaryotic ancestor and only to have been lost by some obligatory intracellular parasites. As such, autophagy represents a unifying biology, subserving survival and the earliest host defense strategies, predating apoptosis, within eukaryotes. Here, we review recent advances in our understanding of autophagic molecular mechanisms and functions in emergent immunity.
PAMPs; DAMPs; autophagy; apoptosis; danger signals; inflammation; programmed cell death
Pancreatic ductal adenocarcinoma (PDA), the fourth leading cause of cancer death in the United States, is a complex disease that arises in the setting of genetic alterations (KRAS, BRCA1, SMAD4, CDKN2A/p16INK4a and TP53), epigenetic perturbations (MIR155, acetylation and methylation) and epicellular events (diabetes and inflammation). We have demonstrated that the advanced glycation end product-specific receptor (AGER, also called RAGE) contributes to pancreatic tumorigenesis. Targeted ablation of AGER diminishes the amount of autophagic flux and attenuates the development of early pancreatic intraepithelial neoplasia (PanIN) lesions in a murine model of KRAS-drivien carcinogenesis. Autophagy (programmed cell survival), a metabolic process of lysosome-mediated self-digestion, promotes pancreatic cancer growth. In pancreatic tumor cell lines, AGER-mediated autophagy promotes interleukin-6 (IL6)-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and mitochondrial localization of pSTAT3. Enhanced mitochondrial pSTAT3 increases the pool of available ATP and increases cellular proliferation. Moreover, we observed a positive feedback loop between activation of autophagy and the IL6-pSTAT3 pathway, perhaps different from the role of cytosolic nonphosphorylated STAT3, which has been reported to inhibit autophagy. These AGER-dependent changes were found during the earliest stages of pancreatic cancer development. These observations of inflammation and altered metabolism in PDA provide a pathological link to early precursor lesion development. Thus, AGER is an important inflammatory mediator that modulates crosstalk between prosurvival pathways, IL6-pSTAT3 and autophagy, in PDA tumor cells, and contributes to early PanIN formation.
RAGE; autophagy; oncogene; KRAS; IL6; STAT3
Double-stranded RNA–dependent protein kinase (PKR) is implicated in inflammation and immune dysfunction through its regulation of mitogen-activated protein kinases, interferon regulatory factor 3, nuclear factorκB, apoptosis, and autophagy pathways. A study shows that PKR is also required for the activation of inflammasomes and the subsequent release of high-mobility group box 1 (HMGB1) protein, a proinflammatory cytokine. Thus, the cell stress kinase PKR has multifaceted roles in the regulation of inflammatory immune responses, and PKR and HMGB1 are attractive targets for inflammasome-associated diseases.
Tumorigenesis and the efficacy of cancer therapeutics are both defined by the balance between autophagy and apoptosis. High-mobility group box 1 (HMGB1) is a DNA chaperone and extracellular damage-associated molecular pattern molecule (DAMP) with pro-autophagic activity. TP53/p53 plays a transcription-dependent and -independent role in the regulation of apoptosis, autophagy, metabolism, cell cycle progression, and many other processes. Both HMGB1 and TP53 are tightly linked with the development of cancer, associated with many of the hallmarks defining the altered biology of cancer. We have demonstrated that TP53-HMGB1 complexes regulate the balance between apoptosis and autophagy through regulation of the cytosolic localization of the reciprocal binding partner, whereby increased cytosolic HMGB1 enhances autophagy and increased cytosolic TP53 enhances apoptosis in colon cancer cells. We found that HMGB1-mediated autophagy promotes cell survival in TP53-dependent processes, and that TP53 inhibits autophagy through negative regulation of HMGB1-BECN1 complexes. Nuclear localization of TP53 and HMGB1 in tumors from patients with colon adenocarcinoma had a positive trend with survival time from diagnosis. Thus, HMGB1 and TP53 are critical in the crossregulation of apoptosis and autophagy and central to colon cancer biology.
Apoptosis; autophagy; colorectal cancer; HMGB1; TP53
The balance between apoptosis (“programmed cell death”) and autophagy (“programmed cell survival”) is important in tumor development and response to therapy. Here we show that HMGB1 and p53 form a complex which regulates the balance between tumor cell death and survival. We demonstrate that knockout of p53 inHCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases autophagy. p53 is thus a negative regulator of the HMGB1/Beclin 1 complex, and HMGB1 promotes autophagy in the setting of diminished p53. HMGB1-mediated autophagy promotes tumor cell survival in the setting of p53-dependent processes. The HMGB1/p53 complex affects the cytoplasmic localization of the reciprocal binding partner thereby regulating subsequent levels of autophagy and apoptosis. These insights provide a novel link between HMGB1 and p53 in the crossregulation of apoptosis and autophagy in the setting of cell stress, providing insights into their reciprocal roles in carcinogenesis.
HMGB1; p53; Autophagy; Apoptosis; Colorectal cancer
IFN1@ (interferon, type 1, cluster, also called IFNα) has been extensively studied as a treatment for patients with chronic myeloid leukemia (CML). The mechanism of anticancer activity of IFN1@ is complex and not well understood. Here, we demonstrate that autophagy, a mechanism of cellular homeostasis for the removal of dysfunctional organelles and proteins, regulates IFN1@-mediated cell death. IFN1@ activated the cellular autophagic machinery in immortalized or primary CML cells. Activation of JAK1-STAT1 and RELA signaling were required for IFN1@-induced expression of BECN1, a key regulator of autophagy. Moreover, pharmacological and genetic inhibition of autophagy enhanced IFN1@-induced apoptosis by activation of the CASP8-BID pathway. Taken together, these findings provide evidence for an important mechanism that links autophagy to immunotherapy in leukemia.
IFN1@; autophagy; apoptosis; immunotherapy; chronic myeloid leukemia
The title co-crystal, [Eu(NCS)3(C18H15OP)3][Eu(NCS)2(NO3)(C18H15OP)3], contains two distinct neutral complexes. Each complex has threefold symmetry about its central Eu3+ ion. As a result, the nitrate-containing molecule contains disorder of its bidentate nitrate and two N-bound thiocyanate anions, while the [Eu(NCS)3(OPPh3)3] complex is fully ordered. There is a weak π–π stacking interaction between the phenyl rings of the two molecules [centroid–centroid distance = 4.138 (4) Å].
The title compound, [Tb(NCS)3(C18H15OP)3], contains a six-coordinate TbII cation surrounded by three O-bound triphenylphosphine oxide ligands and three N-bound thiocyanate ligands, each in a fac arrangement. There are two crystallographically unique TbIII atoms in the asymmetric unit. One TbIII atom resides on a threefold rotation axis, while the other has no imposed crystallographic symmetry. The thiocyanate ligands are bound through N atoms, illustrating the hard–hard bonding principles of metal complex chemistry.
In the title compound, C23H38O5, the oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride unit has a normal geometry and the tetradecoxymethyl side chain is fully extended. In the crystal, molecules are linked head-to-head by C—H⋯O hydrogen bonds, forming two-dimensional networks propagating along the a and c-axis directions.
Reactive oxygen species, including hydrogen peroxide (H2O2), can cause toxicity and act as signaling molecules in various pathways regulating both cell survival and cell death. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated the effect of oxidative stress on activation of the Receptor for Advanced Glycation End-products (RAGE) and subsequent protection against H2O2-induced pancreatic tumor cell damage. We found that exposure of pancreatic tumor cells to H2O2 provoked a nuclear factor kappa B (NF-κB)-dependent increase in RAGE expression. Further, suppression of RAGE expression by RNA interference increased the sensitivity of pancreatic tumor cells to oxidative injury. Furthermore, targeted knockdown of RAGE led to increased cell death by apoptosis and diminished cell survival by autophagy during H2O2-induced oxidative injury. Moreover, we demonstrate that RAGE is a positive feedback regulator for NF-κB as knockdown of RAGE decreased H2O2-induced activity of NF-κB. Taken together, these results suggest that RAGE is an important regulator of oxidative injury. Antioxid. Redox Signal. 15, 2175–2184.
Autophagy, the process by which cells break down spent biochemical and damaged components, plays an important role in cell survival following stress. High mobility group box 1 (HMGB1) regulates autophagy in response to oxidative stress.
Exogenous hydrogen peroxide (H2O2) treatment or knockdown of the major superoxide scavenger enzyme, superoxide dismutase 1 (SOD1), by small interfering RNA (siRNA) increases autophagy in mouse and human cell lines. Addition of either SOD1 siRNA or H2O2 promotes cytosolic HMGB1 expression and extracellular release. Importantly, inhibition of HMGB1 release or loss of HMGB1 decreases the number of autophagolysosomes and autophagic flux under oxidative stress in vivo and in vitro.
HMGB1 release may be a common mediator of response to oxidative stress.
HMGB1 is important for oxidative stress-mediated autophagy and serves as a new target for the treatment of stress-associated disorders. Antioxid. Redox Signal. 15, 2185–2195.
Activation of the induced receptor for advanced glycation endproducts (RAGE) leads to initiation of NF-κB and MAP kinase signaling pathways resulting in propagation and perpetuation of inflammation. RAGE knock out animals are less susceptible to acute inflammation and carcinogen induced tumor development. We have reported that most forms of tumor cell death result in release of the RAGE ligand, HMGB1. We now report a novel role for RAGE in the tumor cell response to stress. Targeted knockdown of RAGE in the tumor cell, leads to increased apoptosis, diminished autophagy and decreased tumor cell survival . In contrast, overexpression of RAGE is associated with enhanced autophagy, diminished apoptosis and greater tumor cell viability. RAGE limits apoptosis through a p53 dependent mitochondrial pathway. Moreover, RAGE-sustained autophagy is associated with decreased phosphorylation of mTOR and increased Beclin-1/VPS34 autophagosome formation. These findings demonstrate that the inflammatory receptor RAGE plays a heretofore unrecognized role in the tumor cell response to stress. Furthermore, these studies establish a direct link between inflammatory mediators in the tumor microenvironment and resistance to programmed cell death. Our data suggest that targeted inhibition of RAGE or its ligands may serve as novel targets to enhance current cancer therapies.
Pancreatic cancer is the fourth most common cancer to cause death due to advanced stage at diagnosis and poor response to current treatment. Autophagy is the lysosome-mediated degradation pathway which plays a critical role in cellular defense, quality control, and energy metabolism. Targeting autophagy is now an exciting field for translational cancer research, as autophagy dysfunction is among the hallmarks of cancer. Pancreatic tumors have elevated autophagy under basal conditions when compared with other epithelial cancers. This review describes our current understanding of the interaction between autophagy and pancreatic cancer development, including risk factors (e.g., pancreatitis, smoking, and alcohol use), tumor microenvironment (e.g., hypoxia and stromal cells), and molecular biology (e.g., K-Ras and p53) of pancreatic cancer. The importance of the HMGB1-RAGE pathway in regulation of autophagy and pancreatic cancer is also presented. Finally, we describe current studies involving autophagy inhibition using either pharmacological inhibitors (e.g., chloroquine) or RNA interference of essential autophagy genes that regulate chemotherapy sensitivity in pancreatic cancer. Summarily, autophagy plays multiple roles in the regulation of pancreatic cancer pathogenesis and treatment, although the exact mechanisms remain unknown.
Autophagy; pancreatic cancer; oncogene; hypoxia; pancreatitis; HMGB1; RAGE; p53; HIF1α; AMPK
Mitochondria are organelles centrally important for bioenergetics as well as regulation of apoptotic death in eukaryotic cells. High mobility group box 1 (HMGB1), an evolutionarily conserved chromatin-associated protein which maintains nuclear homeostasis, is also a critical regulator of mitochondrial function and morphology. We show that heat shock protein beta-1 (HSPB1/ HSP27) is the downstream mediator of this effect. Disruption of the HSPB1 gene in embryonic fibroblasts with wild-type HMGB1 recapitulates the mitochondrial fragmentation, deficits in mitochondrial respiration, and adenosine triphosphate (ATP) synthesis observed with targeted deletion of HMGB1. Forced expression of HSPB1 reverses this phenotype in HMGB1 knockout cells. Mitochondrial effects mediated by HMGB1 regulation of HSPB1 expression, serves as a defense against mitochondrial abnormality, enabling clearance and autophagy in the setting of cellular stress. Our findings reveal a novel role for HMGB1 in autophagic surveillance with important effects on mitochondrial quality control.
microRNAs (miRNAs) are a class of small regulatory RNAs that regulate gene expression at the post-transcriptional level. miRNAs play important roles in the regulation of development, growth, and metastasis of cancer, and in determining the response of tumor cells to anticancer therapy. In recent years, they have also emerged as important regulators of autophagy, a lysosomal-mediated pathway that contributes to degradation of a cell's own components. Imatinib, a targeted competitive inhibitor of the BCR-ABL1 tyrosine kinase, has revolutionized the clinical treatment of chronic myelogenous leukemia (CML). We demonstrate that MIR30A-mediated autophagy enhances imatinib resistance against CML including primary stem and progenitor cells. MIR30A, but not MIR101, is a potent inhibitor of autophagy by selectively downregulating BECN1 and ATG5 expression in CML cells. MIR30A mimics, as well as knockdown of BECN1 and ATG5, increases intrinsic apoptotic pathways. In contrast, the antagomir-30A increases autophagy and inhibits intrinsic apoptotic pathways, confirming that autophagy serves to protect against apoptosis. Taken together, these data clarify some of the underlying molecular mechanisms of tyrosine kinase inhibitor-induced autophagy.
Atg5; autophagy; BCR-ABL tyrosine kinase; Beclin 1; chronic myelogenous leukemia; microRNA
Oxidative stress and associated reactive oxygen species can modify lipids, proteins, carbohydrates, and nucleic acids, and induce the mitochondrial permeability transition, providing a signal leading to the induction of autophagy, apoptosis, and necrosis. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and downstream apoptosis or survival. Accumulation of HMGB1 at sites of oxidative DNA damage can lead to repair of the DNA. As a redox-sensitive protein, HMGB1 contains three cysteines (Cys23, 45, and 106). In the setting of oxidative stress, it can form a Cys23-Cys45 disulfide bond; a role for oxidative homo- or heterodimerization through the Cys106 has been suggested for some of its biologic activities. HMGB1 causes activation of nicotinamide adenine dinucleotide phosphate oxidase and increased reactive oxygen species production in neutrophils. Reduced and oxidized HMGB1 have different roles in extracellular signaling and regulation of immune responses, mediated by signaling through the receptor for advanced glycation end products and/or Toll-like receptors. Antioxidants such as ethyl pyruvate, quercetin, green tea, N-acetylcysteine, and curcumin are protective in the setting of experimental infection/sepsis and injury including ischemia-reperfusion, partly through attenuating HMGB1 release and systemic accumulation. Antioxid. Redox Signal. 14, 1315–1335.
Autophagy is a catabolic process critical to maintaining cellular homeostasis and responding to cytotoxic insult. Autophagy is recognized as “programmed cell survival” in contrast to apoptosis or programmed cell death. Upregulation of autophagy has been observed in many types of cancers and has been demonstrated to both promote and inhibit antitumor drug resistance depending to a large extent on the nature and duration of the treatment-induced metabolic stress as well as the tumor type. Cisplatin, doxorubicin and methotrexate are commonly used anticancer drugs in osteosarcoma, the most common form of childhood and adolescent cancer. Our recent study demonstrated that high mobility group box 1 protein (HMGB1)-mediated autophagy is a significant contributor to drug resistance in osteosarcoma cells. Inhibition of both HMGB1 and autophagy increase the drug sensitivity of osteosarcoma cells in vivo and in vitro. Furthermore, we demonstrated that the ULK1-FIP200 complex is required for the interaction between HMGB1 and BECN1, which then promotes BECN1-PtdIns3KC3 complex formation during autophagy. Thus, these findings provide a novel mechanism of osteosarcoma resistance to therapy facilitated by HMGB1-mediated autophagy and provide a new target for the control of drug-resistant osteosarcoma patients.
osteosarcoma; HMGB1; autophagy; apoptosis; chemotherapy
High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein, which functions as Damage Associated Molecular Pattern molecule (DAMP) when released from cells under conditions of stress, such as injury and infection. Recent studies indicate that HMGB1 plays an important role in leukemia pathogenesis and chemotherapy resistance. Serum HMGB1 is increased in childhood acute lymphocytic leukemia as compared to healthy control and complete remission groups. Moreover, HMGB1 is a negative regulator of apoptosis in leukemia cells through regulation of Bcl-2 expression and caspase-3 activity. As a positive regulator of autophagy, intracellular HMGB1 interacts with Beclin 1 in leukemia cells leading to autophagosome formation. Additionally, exogenous HMGB1 directly induces autophagy and cell survival in leukemia cells. Experimental strategies that selectively target HMGB1 effectively reverse and prevent chemotherapy resistance in leukemia cells, suggesting that HMGB1 is a novel therapeutic target in leukemia.
HMGB1; leukemia; apoptosis; autophagy; chemotherapy
Autophagy and apoptosis are tightly regulated biological processes that are crucial for cell growth, development and tissue homeostasis. UVRAG (UV radiation resistance-associated gene), a mammalian homolog of yeast Vps38, activates the Beclin 1/PtdIns3KC3 (class III phosphatidylinositol-3-kinase) complex, which promotes autophagosome formation. Moreover, UVRAG promotes autophagosome maturation by recruiting class C Vps complexes (HOPS complexes) and Rab7 of the late endosome. We found that UVRAG has anti-apoptotic activity during tumor therapy through interactions with Bax. UVRAG inhibits Bax translocation from the cytosol to mitochondria during chemotherapy- or UV irradiation-induced apoptosis of human tumor cells. Moreover, deletion of the UVRAG C2 domain abolishes Bax binding and anti-apoptotic activity. These results suggest that, in addition to its previously recognized pro-autophagy activity in response to starvation, UVRAG has cytoprotective functions in the cytosol that control the localization of Bax in tumor cells exposed to apoptotic stimuli.
UVRAG; Bax; apoptosis; autophagy; mitochondria; tumor therapy
PML-RARα oncoprotein is a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-α (RARα) and causes acute promyelocytic leukemias (APL). A hallmark of all-trans retinoic acid (ATRA) responses in APL is PML-RARα degradation, which promotes cell differentiation. Here, we demonstrated that autophagy is a crucial regulator of PML-RARα degradation. Inhibition of autophagy by short hairpin (sh) RNA that target essential autophagy genes such as ATG1, ATG5 and PI3KC3, and by autophagy inhibitors (e.g., 3-methyladenine), blocked PML-RARα degradation and subsequently granulocytic differentiation of human myeloid leukemic cells. In contrast, rapamycin, the mTOR kinase inhibitor, enhanced autophagy and promoted ATRA-induced PML-RARα degradation and myeloid cell differentiation. Moreover, PML-RARα co-immunoprecipitated with the ubiquitin-binding adaptor protein p62/SQSTM1, which is degraded through autophagy. Furthermore, knockdown of p62/SQSTM1 inhibited ATRA-induced PML-RARα degradation and myeloid cell differentiation. The identification of PML-RARα as a target of autophagy provides new insight into the mechanism of action of ATRA and its specificity for APL.
autophagy; differentiation; oncoprotein; leukemia; degradation; PML-RARa; p62/SQSTM1
The functional relationship and cross-regulation between autophagy and apoptosis is complex. Here we show that high-mobility group box 1 protein (HMGB1) is a redox-sensitive regulator of the balance between autophagy and apoptosis. In cancer cells, anti-cancer agents enhanced autophagy and apoptosis as well as HMGB1 release. HMGB1 release may be a pro-survival signal for residual cells following various cytotoxic cancer treatments. Diminished HMGB1 by shRNA transfection or inhibition of HMGB1 release by ethyl pyruvate or other small molecules led to predominantly apoptosis and decreased autophagy in stressed cancer cells. In this setting, reducible HMGB1 binds to the receptor for advanced glycation end products (RAGE) but not Toll-like receptor 4 (TLR4), induces Beclin1-dependent autophagy, and promotes tumor resistance to alkylators (melphalan), tubulin disrupting agents (paclitaxel), DNA crosslinkers (ultraviolet light) and DNA-intercalators (oxaliplatin or adriamycin). Oxidized HMGB1 conversely increases the cytotoxicity of these agents and induces apoptosis mediated by the caspase-9/-3 intrinsic pathway. HMGB1 release as well as its redox state thus link autophagy and apoptosis, representing a suitable target when coupled with conventional tumor treatments.
HMGB1 displaces Bcl-2 from Beclin1 to induce and sustain autophagy in response to cell stress.
Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.
High-mobility group box 1 protein (HMGB1), a chromatin associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is an evolutionarily ancient and critical regulator of cell death and survival. Overexpression of HMGB1 is associated with each of the hallmarks of cancer including unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. Our studies and those of our colleagues suggest that HMGB1 is central to cancer (abnormal wound healing) and many of the findings in normal wound healing as well. Here, we focus on the role of HMGB1 in cancer, the mechanisms by which it contributes to carcinogenesis, and therapeutic strategies based on targeting HMGB1.
Damage-associated molecular pattern molecules (DAMPs) are cellularly derived molecules that can initiate and perpetuate immune responses following trauma, ischemia and other types of tissue damage in the absence of pathogenic infection. High mobility group box 1 (HMGB1) is a prototypical DAMP and is associated with the hallmarks of cancer. Recently we found that HMGB1 release after chemotherapy treatment is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to cell death; whereas depletion or inhibition of HMGB1 and autophagy by RNA interference or pharmacological inhibitors increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1 release sustains autophagy as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, degradation of p62 and accumulation of autophagosomes and autolysosomes. Moreover, these data suggest a role for HMGB1 in the regulation of autophagy through the PI3KC3-MEKERK pathway, supporting the notion that HMGB1-induced autophagy promotes tumor resistance to chemotherapy.
DAMP; autophagy; HMGB1; chemotherapy resistance; leukemia; PI3KC3; ERK
The pathogenesis of sepsis is mediated in part by the pathogen-associated molecular pattern molecule bacterial endotoxin, which stimulates macrophages to sequentially release early (e.g., TNF-α, IL-1β) and late (e.g., high-mobility group box [HMGB] 1 protein) proinflammatory mediators. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation into development of several new experimental therapeutics that limit release, either blocking HMGB1 itself or its nominal receptors. Quercetin was recently identified as an experimental therapeutic that significantly protects against oxidative injury. Here, we report that quercetin attenuates lethal systemic inflammation caused by endotoxemia, even if treatment is started after the early TNF response. Quercetin treatment reduced circulating levels of HMGB1 in animals with established endotoxemia. In macrophage cultures, quercetin inhibited release as well as the cytokine activities of HMGB1, including limiting the activation of mitogen-activated protein kinase and NF-κB, two signaling pathways that are critical for HMGB1-induced subsequent cytokine release. Quercetin and autophagic inhibitor, wortmannin, inhibited LPS-induced type-II microtubule-associated protein 1A/1B–light chain 3 production and aggregation, as well as HMGB1 translocation and release, suggesting a potential association between autophagy and HMGB1 release. Quercetin delivery, a strategy to pharmacologically inhibit HMGB1 release that is effective at clinically achievable concentrations, now warrants further evaluation in sepsis and other systemic inflammatory disorders.
quercetin; high-mobility group box 1; sepsis; autophagy