Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a growing appreciation that adipose tissue is a multifunctional organ. In addition to its central role in lipid storage, adipose tissue secretes a diverse group of proteins, called adipokines, involved in lipid metabolism, insulin sensitivity, angiogenesis etc. Adipocytes also secrete various inflammatory and anti-inflammatory mediators. Adiponectin, an adipokine with potent anti-inflammatory properties, is thought to play an important role in the regulation of inflammation. The development of alcoholic liver disease is thought to involve increased pro-inflammatory activity, mediated in part by the activation of Kupffer cells. Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha). Recent studies have demonstrated a hepato-protective effect of adiponectin in the progression of alcoholic liver disease. Herein are summarized recent data demonstrating that adiponectin treatment can normalize LPS-stimulated ROS production and TNF-alpha expression in Kupffer cells after chronic ethanol feeding. These studies suggest that the hepato-protective activity of adiponectin is due, at least in part, to a direct anti-inflammatory effect of adiponectin on Kupffer cells.
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PMID:Regulation of Kupffer cell activity during chronic ethanol exposure: role of adiponectin. 1695 68

Adiponectin is an adipokine with potent anti-inflammatory properties. However, the mechanisms by which adiponectin suppresses macrophage function are not well understood. Treatment of RAW264.7 macrophages with adiponectin for 18 h decreased lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) production. Here we demonstrate that globular adiponectin (gAcrp) initially increased TNF-alpha expression in RAW264.7 macrophages; this TNF-alpha then contributed to increased expression of interleukin-10, which in turn was required for the development of tolerance to subsequent LPS exposure. gAcrp-mediated increases in TNF-alpha mRNA accumulation were associated with increased TNF-alpha promoter activity. gAcrp increased the DNA binding activity of both Egr-1 and NFkappaB; mutation of either the Egr-1 or NFkappaB binding sites in the TNF-alpha promoter decreased gAcrp-stimulated promoter activity. Further, co-transfection with either dominant negative Egr-1 or the IkappaB super-repressor prevented gAcrp-stimulated TNF-alpha promoter activity. gAcrp also increased Egr-1 promoter activity, mRNA accumulation, and DNA binding activity. Inhibition of ERK1/2 with U0126 potently suppressed gAcrp-stimulated Egr-1 promoter activity, as well as TNF-alpha promoter activity. In summary, these data demonstrate that adiponectin initially increases TNF-alpha production by macrophages via ERK1/2-->Egr-1 and NFkappaB-dependent mechanisms; these increases in TNF-alpha in turn lead to increased expression of interleukin-10 and an eventual dampening of LPS-mediated cytokine production in macrophages.
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PMID:Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production. 1753 27

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
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PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46

Obese individuals often have low plasma adiponectin and concomitant chronic inflammation with a predisposition to metabolic and cardiovascular diseases. The present study reports a novel antiinflammatory action of adiponectin in human monocyte-derived macrophages (MPhi) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human MPhi identified CXC chemokine ligands (CXCLs), such as IP-10 (interferon [IFN]-inducible protein 10) (CXCL10), I-TAC (IFN-inducible T-cell alpha chemoattractant) (CXCL11), and Mig (monokine induced by IFN-gamma) (CXCL9), T-lymphocyte chemoattractants associated with atherogenesis, among the top 14 transcripts suppressed by adiponectin. Real-time quantitative RT-PCR and ELISA verified that adiponectin inhibited expression of these chemokines at both the mRNA and protein levels in a concentration-dependent manner. Adiponectin reduced the release by lipopolysaccharide-stimulated MPhi of chemoattractant activity for CXC chemokine receptor 3-transfected (receptor for IP-10, Mig, and I-TAC) lymphocytes. Adiponectin decreased lipopolysaccharide-inducible IP-10 promoter activity in promoter-transfected THP-1 MPhi but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated MPhi, reduction of IFN-beta by adiponectin preceded inhibition of IP-10 mRNA expression. Immunoblot and chromatin immunoprecipitation analyses demonstrated that adiponectin attenuated activation of the transcription factor IFN regulatory factor 3, involved in the MyD88-independent pathway of Toll-like receptor 4 signaling, and subsequent IFN regulatory factor 3 binding to IFN-beta promoter. In vivo studies further demonstrated that apolipoprotein E/adiponectin double-deficient (apoE-/-APN-/-) mice had increased plasma IP-10 levels, accelerated T-lymphocyte accumulation in atheromata, and augmented atherogenesis compared with apoE single-deficient (apoE-/-APN+/+) mice. This study establishes that low levels of adiponectin associated with obesity, the metabolic syndrome, and diabetes favor T-lymphocyte recruitment and contribute to adaptive immune response during atherogenesis.
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PMID:Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. 1823 40

Adiponectin is an adipokine with potent anti-inflammatory properties. The development of alcoholic liver disease is thought to involve increased pro-inflammatory activity, mediated in part by the activation of hepatic macrophages (Kupffer cells). Chronic ethanol feeding sensitizes hepatic macrophages to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species and tumor necrosis factor-alpha (TNF-alpha). Adiponectin can normalize Toll-like receptor-4 (TLR-4) mediated signaling in hepatic macrophages after ethanol feeding, likely contributing to the hepatoprotective effect of adiponectin in the progression of alcoholic liver disease. However, the mechanisms by which adiponectin suppress TLR-4 mediated responses are not well understood. Using the macrophage-like cell line, RAW264.7, we have investigated the molecular mechanisms by which adiponectin suppresses LPS-stimulated TNF-alpha production. Globular adiponectin (gAcrp)-mediated desensitization of LPS-stimulated responses in RAW264.7 macrophages was dependent on the production of the anti-inflammatory cytokine interleukin (IL)-10. gAcrp initially increased TNF-alpha expression in RAW264.7 macrophages; this TNF-alpha then contributed to increased expression of IL-10. This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2-->Egr-1 and nuclear factor (NF)-kappaB-dependent mechanisms. gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter. In summary, these studies reveal a complex, integrated response of macrophages to gAcrp. gAcrp initially activated signaling pathways considered to be pro-inflammatory, with a subsequent increase in the expression of the potent, anti-inflammatory cytokine, IL-10. Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.
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PMID:Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. 1833 64

Adiponectin is an adipokine with potent anti-inflammatory properties. Treatment of macrophages with adiponectin results in a suppression of lipopolysaccharide (LPS)-stimulated cytokine production. Here we investigated the transcriptional and post-transcriptional mechanisms by which adiponectin suppresses LPS-stimulated tumor necrosis factor (TNF)-alpha production. Treatment of RAW 264.7 macrophages with LPS increased TNF-alpha promoter-driven luciferase activity (TNF-alpha promoter/Luc activity) by 20-fold over basal. After culture with 1 mug/ml globular adiponectin (gAcrp) for 18 h, TNF-alpha promoter/Luc activity was increased even in the absence of LPS; further challenge with LPS only increased TNF-alpha promoter/Luc activity by 1.4-fold. Treatment with gAcrp decreased LPS-stimulated ERK1/2 phosphorylation and IkappaB degradation and suppressed the ability of LPS to increase the DNA binding activity of Egr-1 and p65. gAcrp also suppressed LPS-mediated stabilization of TNF-alpha mRNA. In controls cells, the half-life of TNF-alpha mRNA was increased from approximately 30 min at base line to approximately 80 min in response to LPS. After treatment with gAcrp for 18 h, LPS failed to increase TNF-alpha mRNA stability. This gAcrp-mediated loss of stimulus-induced stabilization of TNF-alpha mRNA required the presence of the TNF-alpha 3'-untranslated region and was associated with an increase in expression and RNA binding activity of tristetraprolin, an mRNA-binding protein that destabilizes TNF-alpha mRNA. In summary, these data characterize the complex transcriptional and post-transcriptional effects of gAcrp on LPS-stimulated TNF-alpha expression in macrophages. gAcrp treatment profoundly suppressed the ability of LPS to increase TNF-alpha transcription and reduced the stimulus-induced stabilization of TNF-alpha mRNA in response to LPS.
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PMID:Suppression of lipopolysaccharide-stimulated tumor necrosis factor-alpha production by adiponectin is mediated by transcriptional and post-transcriptional mechanisms. 1867 74

Adiponectin is positively correlated with insulin sensitivity. Hydroxycinnamic acid derivatives (HADs), observed ubiquitously in plants, have some physiological functions. In this study, we investigated the effect of HADs on serum adiponectin concentrations in mice and on adiponectin secretion of 3T3-L1 adipocytes. In mice, serum adiponectin concentrations were increased by gamma-oryzanol administration. CAPE, curcumin, and trans-ferulic acid markedly enhanced the adiponectin secretion of 3T3-L1 adipocytes, but not gamma-oryzanol. To clarify the effects of gamma-oryzanol in mice or the effects of HADs on the underlying mechanisms of adiponectin secretion, we further investigated the effect of HADs on adiponectin secretion in the NF-kappaB activation state. Although the adiponectin secretion was reduced in the presence of lipopolysaccharide plus TNF-alpha and IFN-gamma, only gamma-oryzanol supported the activity of adiponectin secretion under NF-kappaB activated condition. The results indicate that these HADs might regulate adiponectin secretion by the inhibition of NF-kappaB activation. HADs might be effective for ameliorating type 2 diabetes.
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PMID:The effects of hydroxycinnamic acid derivatives on adiponectin secretion. 1901 80

Adiponectin is an adipose-secreted hormone with anti-inflammatory properties mediated by inhibition of nuclear factor-kappaB (NF-kappaB) signaling. This study investigates whether fenofibrate alters adiponectin levels in patients with hypertriglyceridemia and the metabolic syndrome, and examines the association of adiponectin with circulating inflammatory markers and whole blood cytokine production. The effects of fenofibrate (160 mg/day) on adiponectin and other inflammatory markers were investigated in a 12-week randomized, placebo-controlled trial in 55 patients with hypertriglyceridemia (plasma triglycerides > or =1.7 mmol/l and <6.8 mmol/l), central obesity and other characteristics of the metabolic syndrome who were not receiving lipid-altering therapies. In the fenofibrate group, adiponectin levels increased from 4.10 to 4.50 microg/ml (+7.7%); in the placebo group, adiponectin levels increased by 1.8%; (P = 0.0005). In multivariate models including age, gender, and waist circumference, there were inverse correlations between changes in adiponectin and vascular cell adhesion molecule-1 (VCAM-1) (r = -0.54, P < 0.0001) and intercellular adhesion molecule-1 (ICAM-1) (r = -0.57, P < 0.0001), and C-reactive protein (CRP) (r = -0.40, P = 0.0041); lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha) (r = -0.30, P = 0.035), interleukin (IL)-1beta (r = -0.44, P = 0.0016), monocyte chemotactic protein-1 (MCP-1) (r = -0.46, P = 0.001), and macrophage inflammatory protein-1alpha (MIP-1alpha) (r = -0.45, P = 0.0012). Fenofibrate (160 mg/day) raised adiponectin levels in patients with hypertriglyceridemia and the metabolic syndrome. Changes in adiponectin were significantly and inversely associated with changes in multiple inflammatory markers. These data suggest that adiponectin may contribute to the anti-inflammatory effects of fenofibrate.
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PMID:Effect of fenofibrate on adiponectin and inflammatory biomarkers in metabolic syndrome patients. 1902 79

Adiponectin stimulates cholesterol efflux in macrophages and low adiponectin may in part contribute to disturbed reverse cholesterol transport in type 2 diabetes. Monocytes express high levels of annexin A6 that could inhibit cholesterol efflux and it was investigated whether the atheroprotective effects of adiponectin are accompanied by changes in annexin A6 levels. Adiponectin reduces annexin A6 protein whereas mRNA levels are not affected. Adiponectin-mediated activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and AMP-activated protein kinase (AMPK) does not account for reduced annexin A6 expression. Further, fatty acids and lipopolysaccharide that are elevated in obesity do not influence annexin A6 protein levels. Annexin A6 in monocytes from overweight probands or type 2 diabetic patients is significantly elevated compared to monocytes of normal-weight controls. Monocytic annexin A6 positively correlates with body mass index and negatively with systemic adiponectin of the blood donors. Therefore, the current study demonstrates that adiponectin reduces annexin A6 in monocytes and thereby may enhance cholesterol efflux. In agreement with these in vitro finding an increase of monocytic annexin A6 in type 2 diabetes monocytes was observed.
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PMID:Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals and is downregulated by adiponectin in vitro. 1932 30

Adiponectin is an adipokine with potent anti-inflammatory properties. We previously reported that a globular adiponectin (gAd) suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced nuclear factor-kappaB activity, suggesting an anti-inflammatory effect of gAd. In this study, we investigated whether gAd is able to modulate the effect of A. actinomycetemcomitans lipopolysaccharide on cytokine induction in a murine macrophage cell line (RAW 264). The phosphorylation of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and IkappaB kinase alpha/beta and the degradation of IkappaB, which were induced by A. actinomycetemcomitans lipopolysaccharide intoxication, were clearly reduced in gAd-pretreated RAW 264 cells compared with the untreated cells. Expression levels of tumor necrosis factor (TNF)-alpha and interleukin-10 (IL-10) mRNA were assessed by real-time PCR. Cell-free supernatants were collected after 12 h of stimulation and analyzed by enzyme-linked immunosorbent assay for TNF-alpha and IL-10. Pretreatment with gAd significantly inhibited the A. actinomycetemcomitans lipopolysaccharide-induced TNF-alpha mRNA expression and protein secretion. In contrast, pretreatment with gAd significantly enhanced the A. actinomycetemcomitans lipopolysaccharide-induced IL-10 mRNA expression and protein secretion. These data suggest a mechanism for the anti-inflammatory activity of gAd in local inflammatory lesions, such as periodontitis.
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PMID:Anti-inflammatory activity of a globular adiponectin function on RAW 264 cells stimulated by lipopolysaccharide from Aggregatibacter actinomycetemcomitans. 1955 15


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