Suppression of Lipopolysaccharide-stimulated Tumor Necrosis Factor-α Production by Adiponectin Is Mediated by Transcriptional and Post-transcriptional Mechanisms

Park, Pil Hoon; Huang, Honglian; McMullen, Megan R.; Mandal, Palash; Sun, Lei; Nagy, Laura E.

doi:10.1074/jbc.m802787200

Cited by 64 publications

(45 citation statements)

References 59 publications

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“…The mechanism via which adiponectin induces tolerance is still under investigation. It has been recently suggested that this may involve an adiponectin-induced expression of the anti-inflammatory cytokine IL-10 and suppression of TNF-␣ mRNA stability and translation (9,11,13). With this report, we propose an additional mechanism, which associates adiponectin with expression of IRAK-M and tolerance to LPS.…”

Section: Discussionmentioning

confidence: 73%

Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression

Zacharioudaki

Androulidaki²,

Arranz³

et al. 2009

The Journal of Immunology

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High levels of plasma adiponectin are associated with low levels of inflammatory markers and cardioprotection. The mechanism via which adiponectin exerts its anti-inflammatory effect is yet unknown. In the present study, we demonstrate that globular adiponectin (gAd) induces the expression of the inactive isoform of IL-1R-associated kinases (IRAK), IRAK-M. Homologous deletion of IRAK-M in IRAK-M−/− mice abolished the tolerogenic properties of gAd because pretreatment of IRAK-M−/− macrophages with gAd did not suppress LPS-induced proinflammatory cytokine production. GAd activated the MAPKs MEK1/2 and ERK1/2 in macrophages via their upstream regulator Tpl2. Activation of ERK1/2 via Tpl2 appeared necessary for the induction of IRAK-M because gAd did not induce IRAK-M in Tpl2−/− macrophages or in macrophages pretreated with the MEK1/2 inhibitor UO126. In addition, activation of PI3K and Akt1 also appeared necessary for the induction of IRAK-M by gAd, because treatment of Akt1−/− macrophages or pretreatment of macrophages with the PI3K inhibitor wortmannin abolished gAd-induced IRAK-M expression. Analysis of IRAK-M expression in human peripheral blood cells confirmed that serum adiponectin was negatively associated with IRAK-M and responsiveness to LPS. In conclusion, our data demonstrate that IRAK-M is a major mediator of gAd-induced endotoxin tolerance in primary macrophages, expression of which depends on the activation of Tpl2/ERK and PI3K/Akt1 signaling pathways.

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Section: Discussionmentioning

confidence: 73%

Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression

Zacharioudaki

Androulidaki²,

Arranz³

et al. 2009

The Journal of Immunology

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“…In circulation we find that triglycerides, total cholesterol, insulin, and leptin are all significantly elevated in ER␣-deficient animals compared with WT. PAI-1, a surrogate index of systemic inflammation (45,48), is nearly doubled, whereas adiponectin, an adipokine positively associated with insulin sensitivity (43, 73) and inflammation suppression (44,56), is markedly decreased in KO mice. Mean differences between WT vs. KO were detected using ANOVA.…”

Section: Discussionmentioning

confidence: 99%

Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

Ribas

Nguyen

Henstridge

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

270

249

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Ribas V, Nguyen MT, Henstridge DC, Nguyen A, Beaven SW, Watt MJ, Hevener AL. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ER␣-deficient mice. Am J Physiol Endocrinol Metab 298: E304 -E319, 2010. First published November 17, 2009 doi:10.1152/ajpendo.00504.2009.-Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)␣ leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ER␣-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPAR␣, PPAR␦, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ER␣ is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.estrogen receptor-␣; estrogen action; fatty acid metabolism; insulin action INSULIN RESISTANCE IS A CENTRAL FACTOR in the pathogenesis of type 2 diabetes and a defining feature of the metabolic syndrome, a constellation of abnormalities that includes obesity, hypertension, glucose intolerance, and dyslipidemia (21, 50). Prior to menopause, the incidence of type 2 diabetes is lower in women compared with men (50, 57). However, following menopause or ovariectomy this protection is lost, and a precipitous decline in insulin sensitivity coincides with increased fat mass and elevated circulating inflammatory markers [TNF␣, IL-6, and plasminogen activator inhibitor-1 (PAI-1)], LDL, triglycerides, and fatty acids (13,58,66). Similarly, alterations in estrogen receptor (ER) expression in both sexes have been linked with increased prevalence of certain aspects of the metabolic syndrome (22,(53)(54)67). We hypothesize that ER␣ is important in the regulation of tissue substrate metabolism and inflammatory signaling and thus is critical in modulating insulin action and adiposity.It is now widely accepted that impaired fatty acid metabolism and/or fatty acid oversupply cause heightened inflammatory signaling, and these are central contributors to whole body insulin resistance (3,41,84). Accumulation of lipid intermediates in insulin-responsive tissues can activate a host of "stress" kinases,...

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“…Recently, the anti-inflammatory mediators IL-10 and adiponectin were shown to activate TTP. 27,28 In both studies, activation of TTP strongly decreased TNF-␣ levels in response to LPS treatment in macrophages. Mechanistically, TTP activation in response to IL-10 or adiponectin resulted from decreased phosphorylation of TTP by p38-MAPK.…”

Section: Discussionmentioning

confidence: 99%

A Combination of Hypoxia and Lipopolysaccharide Activates Tristetraprolin to Destabilize Proinflammatory mRNAs such as Tumor Necrosis Factor-α

Werno

Schmid

Schnitzer

et al. 2010

The American Journal of Pathology

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Inflammation is often accompanied by hypoxia because of the high oxygen consumption of invading bacteria and immune cells. During resolution of inflammation , the formation of inflammatory mediators such as tumor necrosis factor-␣ (TNF-␣) , which is produced by macrophages , needs to be terminated. We show in RAW264.7 macrophages that TNF-␣ mRNA as well as intracellular and secreted TNF-␣ protein levels are reduced after prolonged incubations with lipopolysaccharide (LPS) under hypoxic conditions. The decrease in TNF-␣ was mediated by destabilization of TNF-␣ mRNA via a 3-untranslated region-dependent mechanism. Specifically , the RNA-binding protein tristetraprolin (TTP) increased at mRNA and protein levels after 16-hour incubations with LPS under hypoxia. Interestingly , TTP accumulated in a dephosphorylated and active form , and this accumulation was attributable to reduced p38 mitogen-activated protein kinase activity under these conditions. Knockdown of TTP by small interfering RNA abolished destabilization of TNF-␣ mRNA. Prolonged incubations with LPS under hypoxia also reduced mRNA amounts and stability of other proinflammatory mediators such as macrophage inflammatory protein-2 , interleukin-6 , and granulocyte macrophage colony-stimulating factor. Therefore , we propose that hypoxia plays a key role during resolution of inflammation by activating posttranscriptional, TTP-dependent regulatory mechanisms.

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Suppression of Lipopolysaccharide-stimulated Tumor Necrosis Factor-α Production by Adiponectin Is Mediated by Transcriptional and Post-transcriptional Mechanisms

Cited by 64 publications

References 59 publications

Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression

Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression

Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

A Combination of Hypoxia and Lipopolysaccharide Activates Tristetraprolin to Destabilize Proinflammatory mRNAs such as Tumor Necrosis Factor-α

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