Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) is a potent, proinflammatory cytokine, but local environmental factors in inflamed sites or in sepsis may affect cell metabolism and energetics, including the amplitude and duration of IL-1-induced signals, thereby leading to loss of tissue homeostasis. Currently, the mechanisms by which disruption of cell energetics affects inflammatory signaling are incompletely understood. Here, we examined the impact of cell energetics and mitochondrial function on the regulation of IL-1-induced Ca2+ signals and ERK activation in human gingival fibroblasts, cells that are important targets for IL-1-induced destruction of extracellular matrix in inflamed connective tissues. In untreated cells, IL-1 induced a prolonged increase of free intracellular calcium, which was required for ERK activation. Inhibition of cellular energetics by selective depolarization of mitochondria blocked Ca2+ uptake and almost completely abolished IL-1-induced cytosolic Ca2+ signals and ERK activation. IL-1 caused rapid Ca2+ release from the endoplasmic reticulum (ER), concomitant with mitochondrial Ca2+ uptake from ER and non-ER stores. Disruption of mitochondrial energetics abrogated IL-1 induced Ca2+ release from the ER but left other vital cellular functions intact. The negative effect of mitochondrial depolarization on ER release was bypassed by BAPTA/AM, indicating that mitochondrial Ca2+ buffering is the key mechanism in regulating ER release. Thus, in gingival fibroblasts, mitochondrial Ca2+ uptake is essential not only for shaping the kinetics and duration, but also the generation of, IL-1-induced Ca2+ signals. Consequently, mitochondria regulate key downstream effectors of IL-1, including MAP kinases.
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PMID:Mitochondrial function is a critical determinant of IL-1-induced ERK activation. 1572 61

Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappaB and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2-/-, and myeloid differentiation factor 88-/- (MyD88-/-) macrophages and completely abolished in TLR2-/-/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.
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PMID:The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. 1602 56

Glutamine (GLN) has been shown to attenuate cytokine release from LPS-stimulated human peripheral blood mononuclear cells; however, the in vivo antiinflammatory effect of GLN in polymicrobial sepsis and ARDS is unknown. This study evaluates the effect of GLN on inflammatory cytokine release and the pathways that may mediate antiinflammatory effects of GLN in the lung. Either 0.75 g/kg of GLN or saline placebo (SP) was administered to male rats 1 h after cecal ligation and puncture (CLP). NF-kappaB activation, IKBalpha degradation, phosphorylation of p38 MAPK, ERK, and MKP-1 expression were evaluated in lung tissue 6 h post-CLP. Lung tissue iNOS and eNOS, TNF-alpha, IL-6, and IL-18 cytokines were assayed. Last, lung histopathology for occurrence of ARDS and survival were examined. GLN given 1 h postsepsis led to inhibition of lung tissue NF-kappaB activation (P < 0.001 vs. SP), attenuated degradation of IKBalpha, and inhibited phosphorylation of p38 MAPK, and ERK, pathways critical for cytokine release. GLN treatment increased MKP-1 peptide expression and significantly attenuated TNF-alpha and IL-6 6 h after CLP. IL-18 was attenuated by GLN at multiple time points post-CLP. Further, GLN abrogated increases in lung iNOS expression and enhanced lung eNOS postsepsis. Finally, GLN prevented the histopathologic appearance of ARDS after sepsis and significantly improved survival. These data reveal that GLN exerts an antiinflammatory effect in sepsis that may be mediated via attenuation of multiple pathways of inflammation such as NF-kappaB, p38 MAPK, ERK, and MKP-1. GLN also showed an inhibition of increases in iNOS expression. The antiinflammatory effect of GLN was associated with attenuation of ARDS and mortality.
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PMID:GLUTAMINE PREVENTS ACTIVATION OF NF-kappaB AND STRESS KINASE PATHWAYS, ATTENUATES INFLAMMATORY CYTOKINE RELEASE, AND PREVENTS ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) FOLLOWING SEPSIS. 1631 91

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-gamma to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.
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PMID:Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. 1700 95

Staphylococcus aureus, a major sepsis-causing Gram-positive bacterium, invades pulmonary epithelial cells and causes lung diseases. In the lung, alveolar type II epithelial cells play an important role in innate immunity by secreting chemokines and antimicrobial peptides upon bacterial infection whereas type I cells mainly function in gas-exchange. In this study, we investigated the ability of S. aureus peptidoglycan (PGN) to induce expression of a chemokine, IL-8, in a human alveolar type II epithelial cell line, A549. PGN induces IL-8 mRNA and protein expression in a dose- and time-dependent manner. Supplementation of soluble CD14 further enhanced the PGN-induced IL-8 expression. Interestingly, PGN-induced IL-8 expression was inhibited by nystatin, a specific inhibitor for lipid rafts, but not by chlorpromazine, a specific inhibitor for clathrin-coated pits. Furthermore, PGN-induced IL-8 expression was attenuated by inhibitors for MAP kinases such as ERK, p38 kinase, and JNK/SAPK, whereas no inhibitory effect was observed by inhibitors for reactive oxygen species or protein kinase C. Electrophoretic mobility shift assay demonstrates that PGN increased the DNA binding of the transcription factors, AP-1 and NF-kappaB while minimally, NF-IL6, all of which are involved in the transcription of IL-8. Taken together, these results suggest that PGN induces IL-8 expression in a CD14-enhanced manner in human alveolar type II epithelial cells, through the formation of lipid rafts and the activation of MAP kinases, which ultimately leads to activation of AP-1, NF-kappaB, and NF-IL6.
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PMID:Peptidoglycan-mediated IL-8 expression in human alveolar type II epithelial cells requires lipid raft formation and MAPK activation. 1799 61

Alcohol (EtOH) intoxication and burn injury independently activate hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoids, the end product of the HPA axis, play a role in shaping the immune response under those conditions. By utilizing a rat model of acute EtOH intoxication and burn injury, studies in our laboratory have investigated the role of corticosterone (i.e., glucocorticoids in rodents) in altered intestinal immunity and barrier function following a combined insult of EtOH and burn injury. Results from these studies suggest that EtOH intoxication prior to burn injury augments corticosterone release, which in turn suppresses intestinal T cell function by inhibiting mitogen-activated protein kinase (i.e., p38 and ERK) pathway. Furthermore, we found that corticosterone does not directly alter the intestinal barrier function; rather, it up-regulates interleukin-18, which then directly or indirectly contributes to impaired intestinal barrier function. The loss of intestinal immunity/barrier function may result in increased bacterial translocation and thereby contribute to postinjury pathogenesis, leading to sepsis and organ dysfunction in burn patients as well as in patients with a history of EtOH intoxication.
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PMID:A role for corticosterone in impaired intestinal immunity and barrier function in a rodent model of acute alcohol intoxication and burn injury. 1804 Aug 15

Propofol (PPF), a widely used intravenous anesthetic for induction and maintenance of anesthesia during surgeries, was found to possess suppressive effect on host immunity. This study aimed at investigating whether PPF plays a modulatory role in the lipopolysaccharide (LPS)-induced inflammatory cytokine expression in a cell line of rat hepatocytes. Morphological observation and viability assay showed that PPF exhibits no cytotoxicity at concentrations up to 300 microM after 48 h incubation. Pretreatment with 100 microM PPF for 24 h prior to LPS stimulation was performed to investigate the modulatory effect on LPS-induced inflammatory gene production. The results of semi-quantitative RT-PCR demonstrated that PPF pretreatment significantly suppressed the LPS-induced toll-like receptor (TLR)-4, CD14, tumor necrosis factor (TNF)-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression. Western blotting analysis showed that PPF pretreatment potentiated the LPS-induced TLR-4 downregulation. Flow cytometrical analysis revealed that PPF pretreatment showed no modulatory effect on the LPS-upregulated CD14 expression on hepatocytes. In addition, PPF pretreatment attenuated the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and IkappaBalpha, as well as the nuclear translocation of NF-kappaB primed by LPS. Moreover, addition of PD98059, a MAPK kinase inhibitor, significantly suppressed the LPS-induced NF-kappaB nuclear translocation and GM-CSF production, suggesting that the PPF-attenuated GM-CSF production in hepatocytes may be attributed to its suppressive effect on MAPK/ERK signaling pathway. In conclusion, PPF as an anesthetic may clinically benefit those patients who are vulnerable to sepsis by alleviating sepsis-related inflammatory response in livers.
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PMID:Propofol pretreatment attenuates LPS-induced granulocyte-macrophage colony-stimulating factor production in cultured hepatocytes by suppressing MAPK/ERK activity and NF-kappaB translocation. 1838 47

The systemic inflammatory response syndrome (SIRS) is triggered by lipopolysaccharide (LPS) from Gram-negative bacteria. Insulin was shown to have a protective role in SIRS related to sepsis. Lungs are particularly affected in this condition and provide a second wave of mediators/cytokines which amplifies SIRS. The aim of the present study was to investigate the effect of insulin on the signaling pathways elicited by LPS in alveolar macrophages (AMs) and its consequence in cellular response to LPS measured as production of tumor necrosis factor (TNF). To this purpose, resident AMs from male Wistar rats were obtained by lung lavage and stimulated by LPS (100 ng/mL). Insulin (1 mU/mL) was added 10 min before LPS. Activation (phosphorylation) of signaling molecules by LPS was analyzed by western blot, 30 min after LPS stimulation. TNF was measured in the AMs culture supernatants by bioassay using L-929 tumor cells. Relative to controls, LPS induced a significant increase in the activation of ERK (3.6-fold), p38 (4.4-fold), Tyr-326 Akt (4.7-fold), Ser-473 Akt (6.9-fold), PKCalpha (4.7-fold) and PKCdelta (2.3-fold). Treatment of AMs with insulin before LPS stimulation, significantly reduced the activation of ERK (54%), p38 (48%), Tyr-326 Akt (64%), Ser-473 Akt (41%), PKCalpha (62%) and PKCdelta (39%). LPS induced TNF production in AMs which was also inhibited by insulin (60%). These results show that insulin down-regulates MAPK, PI3K and PKCs and inhibits a downstream effect of LPS, TNF production, in rat AMs stimulated with LPS and suggest that the protective effect of insulin in sepsis could be through modulation of signal transduction pathways elicited by LPS in lung macrophages.
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PMID:Insulin inhibits LPS-induced signaling pathways in alveolar macrophages. 1844 18

Redox regulation of inducible nitric oxide synthase (iNOS) expression was investigated in lipopolysaccharide and interferon-gamma (LPS + IFNgamma)-stimulated microvascular endothelial cells from mouse skeletal muscle. Unstimulated endothelial cells produced reactive oxygen species (ROS) sensitive to inhibition of NADPH oxidase (apocynin and DPI), mitochondrial respiration (rotenone) and NOS (L-NAME). LPS + IFNgamma caused a marked increase in ROS production; this increase was abolished by inhibition of NADPH oxidase (apocynin, DPI and p47phox deficiency). LPS + IFNgamma induced substantial expression of iNOS protein. iNOS expression was prevented by the antioxidant ascorbate and by NADPH oxidase inhibition (apocynin, DPI and p47phox deficiency), but not by inhibition of mitochondrial respiration (rotenone) and xanthine oxidase (allopurinol). iNOS expression also was prevented by selective antagonists of ERK, JNK, Jak2, and NFkappaB activation. LPS + IFNgamma stimulated activation/phosphorylation of ERK, JNK, and Jak2 and activation/degradation of IkappaB, but only the activation of JNK and Jak2 was sensitive to ascorbate, apocynin and p47phox deficiency. Ascorbate, apocynin and p47phox deficiency also inhibited the LPS + IFNgamma-induced DNA binding activity of transcription factors IRF1 and AP1 but not NFkappaB. In conclusion, LPS + IFNgamma-induced NFkappaB activation is necessary for iNOS induction but is not dependent on ROS signaling. LPS + IFNgamma-stimulated NADPH oxidase activity produces ROS that activate the JNK-AP1 and Jak2-IRF1 signaling pathways required for iNOS induction. Since blocking either NFkappaB activation or NADPH oxidase activity is sufficient to prevent iNOS expression, they are separate targets for therapeutic interventions that aim to modulate iNOS expression in sepsis.
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PMID:iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. 1848 Dec 58

Nucleotide receptors serve as sensors of extracellular ATP and are important for immune function. The nucleotide receptor P2RX7 is a cell-surface, ligand-gated cation channel that has been implicated in many diseases, including arthritis, granuloma formation, sepsis, and tuberculosis. These disorders are often exacerbated by excessive mediator release from activated macrophages in the inflammatory microenvironment. Although P2RX7 activation can modulate monocyte/macrophage-induced inflammatory events, the relevant molecular mechanisms are poorly understood. Previous studies suggest that MAPK cascades and transcriptional control via CREB-linked pathways regulate the inflammatory capacity of monocytic cells. As P2RX7 promotes MAPK activation and inflammatory mediator production, we examined the involvement MAPK-induced CREB activation in P2RX7 action. Our data reveal that stimulation of multiple monocytic cell lines with P2RX7 agonists induces rapid CREB phosphorylation. In addition, we observed a lack of nucleotide-induced CREB phosphorylation in RAW 264.7 cells expressing nonfunctional P2RX7 and a gain of nucleotide-induced CREB phosphorylation in human embryonic kidney-293 cells that heterologously express human P2RX7. Furthermore, our results indicate that P2RX7 agonist-induced CREB phosphorylation is partly mediated via Ca(2+) fluxes and the MEK/ERK system. Mechanistic analyses revealed that macrophage stimulation with a P2RX7 agonist induces CREB/CREB-binding protein complex formation, which is necessary for CREB transcriptional activation. Also, we demonstrate that P2RX7 activation induces a known CREB-dependent gene (c-fos) and that dominant-negative CREB constructs attenuate this response. These studies support the idea that P2RX7 stimulation can directly regulate protein expression that is not dependent on costimulation with other immune modulators such as LPS.
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PMID:The nucleotide receptor P2RX7 mediates ATP-induced CREB activation in human and murine monocytic cells. 1862 10


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