Adiponectin Enhances IL-6 Production in Human Synovial Fibroblast via an AdipoR1 Receptor, AMPK, p38, and NF-κB Pathway

Tang, Chih‐Hsin; Chiu, Yung-Cheng; Tan, Tzu-Wei; Yang, Rong‐Sen; Fu, Wen‐Mei

doi:10.4049/jimmunol.179.8.5483

Cited by 237 publications

(235 citation statements)

References 47 publications

(60 reference statements)

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“…39 Our results showed that genistein induced adiponectin production but downregulated p38, p65 and IL-6. These results suggest that genistein may downregulate the negative effects adiponectin by inhibiting p38 and NF-kB pathways.…”

Section: Discussionmentioning

confidence: 56%

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Relić

Zeddou

Desoroux

et al. 2009

Laboratory Investigation

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It was shown recently that synovial fibroblast transformation into adipocytes reduced the expression of interleukin-6 (IL-6) and IL-8. However, the synovial fibroblast adipogenesis was inhibited in inflammatory conditions induced by the tumor necrosis factor-a (TNF-a). Furthermore, adipogenesis is often accompanied by leptin production, a proinflammatory adipokine in rheumatic diseases. In this study, we tested the phytohormone genistein for adipogenic and anti-inflammatory properties on human synovial fibroblasts. Results showed that genistein was able to transform synovial fibroblasts into adipocytes that expressed perilipin-A and produced adiponectin, but not leptin. Furthermore, genistein enhanced glucocorticoid-mediated synovial fibroblast adipogenesis and, in parallel, downregulated glucocorticoid-induced leptin and leptin receptor. Endogenous and TNF-a-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-b were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferatoractivated receptor-g (PPAR-g) agonist, rosiglitazone, had a synergic effect on genistein-induced adipogenesis, whereas the non-active tyrosine kinase inhibitor, daidzein, had a significantly inferior adipogenic activity than genistein. The Janus kinase-2 tyrosine kinase inhibitor, AG 490, mimicked the anti-leptin effect of genistein. These results showed that genistein-induced adipogenesis involves PPAR-g induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.

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Section: Discussionmentioning

confidence: 56%

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Relić

Zeddou

Desoroux

et al. 2009

Laboratory Investigation

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“…Yet, despite these studies, the role of AMPK in immunity is not exclusively anti-inflammatory. Addition of the AMPK inhibitor Compound C suppressed IFN-␤ induction in response to cytosolic nucleic acids (39) and IL-6 secretion in response to adiponectin (62), showing that AMPK can also induce a pro-inflammatory response in certain instances.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-␤ induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-␤ and TNF-␣ induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-␤ and TNF-␣ after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-␤ in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells.Pathogen sensing by innate immune cells is essential for host defense in response to invading microorganisms. Recognition by pattern recognition receptors typically activates signal transduction pathways, leading to up-regulation of cytokines like TNF-␣ and IFN-␤. Although IFN-␤ has a well established role in defense against viral infection, intracellular bacterial infections also induce this cytokine. In the past decade, our understanding of the molecular basis for these signaling pathways has expanded greatly and it has been discovered that there is some overlap between proteins responsible for recognition of bacteria and virus alike. One particular example is the mitochondrial and endoplasmic reticulum resident protein stimulator of interferon genes (STING) 2 (1-3). STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7-12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13-15). This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is piv...

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“…While clear evidence derived from knockdown of adiponectin's specific receptors (Adipo R1 and Adipo R2) shows that immunomodulatory actions of adiponectin are mediated through these receptors [38,39], we believe that LPS contamination may contribute under certain circumstances and should be considered. Several other factors are now recognized as contributing to the emerging complexity of adiponectin's immunomodulatory signalling.…”

Section: Discussionmentioning

confidence: 99%

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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Adiponectin Enhances IL-6 Production in Human Synovial Fibroblast via an AdipoR1 Receptor, AMPK, p38, and NF-κB Pathway

Cited by 237 publications

References 47 publications

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

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

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