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IL-6 and TNF-? induced obesity-related inflammatory response through transcriptional regulation of miR-146b.

ABSTRACT: Obesity is associated with a low-grade inflammation of white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance, and even diabetes. MicroRNAs (miRNAs) have been implicated as negative regulators controlling diverse biological processes at the level of post-transcriptional repression. miR-146b is an intergenic miRNA that can regulate the inflammatory process by attenuating cytokine signaling via the nuclear factor-?B pathway. In this study, we focused on investigating the expression of miR-146b in mature human adipocytes and their response to proinflammatory cytokines. Our results showed that miR-146b was highly expressed in the mature adipocytes. The mature human adipocytes responded to proinflammatory cytokines (TNF-? and IL-6) by highly increasing the expression of miR-146b. We cloned and identified a potential promoter of the transcriptional regulation of miR-146b. Interestingly, a fragment about 950-bp length upstream sequences of miR-146b had apparent transcription activity. In addition, the increase in miR-146b promoter activity by TNF-? and IL-6 was also effectively elevated. Our results indicated that a novel role for miR-146b in adipose tissue inflammation and miR-146b may be an important mediator in the process of obesity complications via its own transcription mechanism.

SUBMITTER: Shi C

PROVIDER: S-EPMC4015473 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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IL-6 and TNF-α induced obesity-related inflammatory response through transcriptional regulation of miR-146b.

Shi Chunmei C Zhu Lijun L Chen Xiaohui X Gu Nan N Chen Ling L Zhu Lu L Yang Lei L Pang Lingxia L Guo Xirong X Ji Chenbo C Zhang Chunmei C

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20140115 5

Obesity is associated with a low-grade inflammation of white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance, and even diabetes. MicroRNAs (miRNAs) have been implicated as negative regulators controlling diverse biological processes at the level of post-transcriptional repression. miR-146b is an intergenic miRNA that can regulate the inflammatory process by attenuating cytokine signaling via the nuclear factor-κB pathway. In this study, we focused on ...[more]

PMID: 24428800

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Project description:INTRODUCTION:The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNF? and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. METHODS:SF lines were stimulated with either TNF?, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value <?0.05 was considered statistically significant. RESULTS:The stimulation of SF with IL6/sIL6R and TNF?, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNF? and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. CONCLUSIONS:These results point out to a highly orchestrated response to IL6 in TNF?-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

Project description:BackgroundLow adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NF?B pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NF?B-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin.MethodsmiR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes.ResultsmiR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NF?B p65 DNA binding activity and TNF?. As a response IRAK3 and IRS1 protein increased. Mitochondrial and intracellular ROS production did not increase despite more inflammation. In addition, exposure of miR-146b-5p-depleted THP-1 monocytes to high levels of globular adiponectin resulted in an increased production of TNF? and intracellular ROS. Still, they did not lose their potential to increase IRAK3 and IRS1 protein and to decrease mitochondrial ROS.ConclusionmiR-146b-5p, decreased in monocytes during obesity, is a major mediator of the anti-inflammatory action of globular adiponectin. It appears not to be involved in insulin signaling possibly by protective response of IRAK3 and lack of mitochondrial ROS production.

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IL-6 and TNF-? induced obesity-related inflammatory response through transcriptional regulation of miR-146b.

Publications

IL-6 and TNF-α induced obesity-related inflammatory response through transcriptional regulation of miR-146b.

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