Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli

Tsatsanis, Christos; Zacharioudaki, Vassiliki; Androulidaki, Ariadne; Dermitzaki, Eleni; Charalampopoulos, Ioannis; Minas, Vassilis; Gravanis, Achille; Margioris, Andrew N.

doi:10.1016/j.bbrc.2005.07.197

Cited by 185 publications

(170 citation statements)

References 38 publications

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“…In addition, adipose tissue mRNA levels and plasma concentrations of TNF-␣ and adiponectin have been reported to be negatively correlated in nondiabetic subjects (14). Given the fact that some studies also found a somewhat surprising upregulation of TNF-␣ by adiponectin in their in vitro systems (31,32), the biological relevance of our finding remains to be elucidated. Regarding the relation of eotaxin with adiponectin, there were positive but nonsignificant trends in the first analysis, which stratified the sample into subjects with NGT and IGT/type 2 diabetes.…”

Section: Statistical Analysesmentioning

confidence: 62%

Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?

et al. 2006

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OBJECTIVE -Previous studies have yielded conflicting results on the association of adiponectin levels and inflammation. Low systemic concentrations of adiponectin, as well as elevated levels of immune mediators, represent risk factors for the development of type 2 diabetes and coronary artery disease. The major aim of this cross-sectional study was to investigate the interdependence of hypoadiponectinemia and low-grade systemic inflammation. ; 1999 -2001). Systemic concentrations of adiponectin and a wide range of anthropometric, metabolic, and inflammatory variables were available for analyses. The association of adiponectin with 15 immunological markers, including leukocyte count, acute-phase proteins, cytokines, cytokine receptors, and chemokines, was assessed using univariable and multivariable models. RESEARCH DESIGN AND METHODSRESULTS -No evidence for a significant correlation between adiponectin and all immunological parameters except eotaxin could be found after multivariable adjustments, whereas multiple strong correlations with obesity and metabolic factors were present.CONCLUSIONS -From these data, we conclude that hypoadiponectinemia and a proinflammatory state are largely independent from each other.

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Section: Statistical Analysesmentioning

confidence: 62%

Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?

et al. 2006

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“…In vitro models have suggested that the immunomodulatory actions of adiponectin are anti-inflammatory [8][9][10][11][12][13][14], as exemplified by its in vitro ability to attenuate lipopolysaccharide (LPS) induction of tumour necrosis factor (TNF-a) [8,14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it has also been reported that adiponectin induces the inflammatory cytokines, interleukin (IL)-6 and TNF-a in some systems [15,21,22]. One hypothesis proposed to reconcile this apparent paradox postulates stable high circulating levels of adiponectin, typically seen in lean healthy individuals [23], and may induce tolerance to the pro-inflammatory effects of adiponectin and to other inflammatory stimuli including Toll-like receptor (TLR) ligands such as LPS [15,24].…”

Section: Introductionmentioning

confidence: 99%

“…One hypothesis proposed to reconcile this apparent paradox postulates stable high circulating levels of adiponectin, typically seen in lean healthy individuals [23], and may induce tolerance to the pro-inflammatory effects of adiponectin and to other inflammatory stimuli including Toll-like receptor (TLR) ligands such as LPS [15,24]. However, adiponectin itself avidly binds LPS [25] with the result that producing totally LPS-free recombinant adiponectin is technically very challenging.…”

Section: Introductionmentioning

confidence: 99%

“…heat shock protein 60 [26]). Furthermore, there are several similarities between some immunomodulatory effects of adiponectin and the phenomena of LPS tolerance [27], specifically the ability of adiponectin to induce tolerance to LPS [15] and to other TLR ligands [24] as well as the necessity to pre-incubate cells with adiponectin for several hours prior to stimulation to observe attenuation of TNF induction [15,24].…”

Section: Introductionmentioning

confidence: 99%

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Induction of TLR Tolerance in Human Macrophages by Adiponectin: Does LPS Play a Role?

et al. 2009

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Obesity is regarded as a pro‐inflammatory state. It is associated with low circulating levels of the adipokine, adiponectin, which is considered to be an anti‐inflammatory. However, adiponectin knockout mice do not consistently demonstrate pro‐inflammatory phenotypes, suggesting more complexity in the in vivo immunomodulatory effects of adiponectin than originally anticipated. Moreover, adiponectin exerts pro‐inflammatory effects in some experimental systems. This contradiction has been resolved by hypothesizing that adiponectin induces tolerance to inflammatory stimuli, notably Toll‐like receptor (TLR) ligands. We noticed that this effect resembled lipopolysaccharide (LPS) tolerance and therefore tested adiponectin from a variety of sources for LPS contamination. All adiponectin tested carried low levels of LPS in the range of 1–30 pg/μg of adiponectin, sufficient to produce final LPS concentrations in the pg/ml range under experimental conditions. We found that induction of tolerance to TLR ligands by adiponectin in human monocyte‐derived macrophages could be reproduced by such LPS concentrations. Moreover, the LPS antagonist, polymixin B, substantially inhibited induction of tolerance by adiponectin. Furthermore, polymixin B and a naturally occurring antagonist LPS were able to partially attenuate induction of tumour necrosis factor‐α and interleukin‐6 in human monocyte‐derived macrophages by adiponectin. Polymixin B also inhibited nuclear factor‐κB and mitogen‐activated protein kinase signalling elicited by adiponectin. We therefore propose that some of adiponectin’s immunomodulatory effects, in particular, its TLR‐tolerising actions in human monocyte‐derived macrophages, may be confounded by induction of tolerance by contaminating LPS.

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Critical role of tristetraprolin and AU‐rich element RNA‐binding protein 1 in the suppression of cancer cell growth by globular adiponectin

et al. 2018

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Adiponectin exhibits potent antitumor activities. Herein, we examined the molecular mechanisms underlying suppression of tumor growth by globular adiponectin ( gA crp). We demonstrated that gA crp suppressed B‐cell lymphoma 2 (Bcl‐2) expression, an anti‐apoptotic gene, by inducing its mRNA destabilization, which was accompanied with a decrease in cell viability and increased caspase‐3 activity in hepatic cancer cells. In addition, gA crp increased expression of tristetraprolin ( TTP ) and AU‐rich element RNA‐binding protein 1 ( AUF 1), which are mRNA stability regulatory proteins. Moreover, gA crp‐induced suppression of Bcl‐2 expression was abrogated by knockdown of TTP or AUF 1. These data indicate that gA crp induces apoptosis of hepatic cancer cells by TTP ‐ and AUF 1‐mediated Bcl‐2 mRNA destabilization, and further suggest that TTP and AUF 1 are novel targets mediating the antitumor activity of adiponectin.

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Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli

Cited by 185 publications

References 38 publications

Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?

Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?

Induction of TLR Tolerance in Human Macrophages by Adiponectin: Does LPS Play a Role?

Critical role of tristetraprolin and AU‐rich element RNA‐binding protein 1 in the suppression of cancer cell growth by globular adiponectin

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