Leptin Induces IL-6 Expression through OBRl Receptor Signaling Pathway in Human Synovial Fibroblasts

Yang, Wei-Hung; Liu, Shan‐Chi; Tsai, Chun‐Hao; Fong, Yi‐Chin; Wang, Shoou-Jyi; Chang, Ya-Wen; Tang, Chih-Hsin

doi:10.1371/journal.pone.0075551

Cited by 69 publications

(60 citation statements)

References 45 publications

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“…It has been well-established that obesity promotes leptin resistance28. A recent report further demonstrates that leptin up-regulates IL-6 expression in human synovial fibroblasts, suggesting its role in joint inflammation29. Interestingly, we found that pentadecylic acid also showed a positive correlation with ear wound healing and serum adiponectin levels.…”

Section: Discussionsupporting

confidence: 61%

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair

Kimmerling

Little

et al. 2017

Sci Rep

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High-fat diet-induced obesity is a major risk factor for osteoarthritis (OA) and diminished wound healing. The objective of this study was to determine the associations among serum and synovial fluid lipid levels with OA, synovitis, adipokine levels, and wound healing in a pre-clinical obese mouse model of OA. Male C57BL/6 J mice were fed either a low-fat (10% kcal) or one of three high-fat (HF, 60% kcal) diets rich in saturated fatty acids (SFAs), ω-6 or ω-3 polyunsaturated FAs (PUFAs). OA was induced by destabilization of the medial meniscus. Mice also received an ear punch for evaluating wound healing. Serum and synovial fluid were collected for lipidomic and adipokine analyses. We demonstrated that the serum levels of ω-3 PUFAs were negatively correlated with OA and wound size, but positively correlated with adiponectin levels. In contrast, most ω-6 PUFAs exhibited positive correlations with OA, impaired healing, and inflammatory adipokines. Interestingly, levels of pentadecylic acid (C15:0, an odd-chain SFA) and palmitoleic acid were inversely correlated with joint degradation. This study extends our understanding of the links of FAs with OA, synovitis and wound healing, and reports newly identified serum and synovial fluid FAs as predictive biomarkers of OA in obesity.

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Section: Discussionsupporting

confidence: 61%

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair

Kimmerling

Little

et al. 2017

Sci Rep

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“…In this study, we demonstrated that leptin‐induced proliferation required ERK1/2 activation. This pathway has been widely studied as it is thought to be activated by virtually all mitogenic factors (Yang et al ., ). ERK1/2 is indeed a key regulator of the early cell cycle induction, as it is involved in G0/G1 and G1/S transition and our team demonstrated a key role for the biphasic transient activation of ERK1/2 in mymetrial cell proliferation (Hadi et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…Both leptin and its receptors share structural and functional similarities with the IL-6 receptor family; leptin stimulated leptin receptors are known to activate the three main signalling pathways that are activated by the IL-6 receptor: the JAK/STAT (not activated by short isoforms), PI3K/Akt and ERK1/2 pathways (Fruhbeck, 2006). However, it has been shown that IL-6 is also able to activate the NF-κB pro-inflammatory signalling pathway after binding to its receptor (Yang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

Barrichon

Hadi

Wendremaire

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSELeptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence. EXPERIMENTAL APPROACHWe stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptor antagonists or signalling pathway inhibitors. KEY RESULTSLeptin induced myometrial cell proliferation in a biphasic manner. At 6.25 ng·mL , leptin induced direct non-specific stimulation of the IL-6 receptor, leading to NF-κB activation, and exerted anti-proliferative effects. However, at 50 ng·mL, leptin re-induces proliferation via IL-6 receptor stimulation that requires STAT3 and delayed ERK1/2 activation. CONCLUSIONS AND IMPLICATIONSThese data bring new insights into leptin signalling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6 receptor axis. In the light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of PTL and it also strengthens the hypothesis that leptin might be a contributory factor in the parturition-related disorders observed in obese women.

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“…These intimal lining cells express adiponectin and leptin receptors and are thus able to respond to SF adipokines (5,6,8). Few data have shown up-regulation of IL-6 and IL-8 in FLS by leptin, but a significant effect was observed at high, non-physiological (μg/mL) leptin concentrations (6,8). In vitro data suggest that adiponectin contributes to joint inflammation and destruction.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, adiponectin and leptin produced in rheumatoid joints may impact local pathology and the results of in vitro studies suggest their proinflammatory and pro-destructive role (3). However, these data are scarce and in some studies very high concentrations of leptin and adiponectin were used (4)(5)(6)(7)(8). Therefore, it is uncertain whether in vivo adipokines possess the reported activities.…”

Section: Please Scroll Down For Articlementioning

confidence: 99%

The effect of multimeric adiponectin isoforms and leptin on the function of rheumatoid fibroblast-like synoviocytes

Kontny¹,

Janicka²,

Skalska³

et al. 2015

Scandinavian Journal of Rheumatology

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Leptin Induces IL-6 Expression through OBRl Receptor Signaling Pathway in Human Synovial Fibroblasts

Cited by 69 publications

References 45 publications

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

The effect of multimeric adiponectin isoforms and leptin on the function of rheumatoid fibroblast-like synoviocytes

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