TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

Doig, Craig; Bashir, Jamila; Zielińska, Agnieszka; Cooper, Mark S.; Stewart, Paul M.; Lavery, Gareth G.

doi:10.1530/joe-13-0494

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…Finally, three pairs of primers (Table 1) were prepared to amplify regions (-2303/-2289, -1780/-1771, -145/-127). IκBα was used as a positive control, and its primers were obtained from the literature (Doig et al, 2014). ChIP-qPCR data was normalized with a fold enrichment method.…”

Section: Chromatin Immunoprecipitation (Chip) Assaysmentioning

confidence: 99%

p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes

Jin

et al. 2016

Gene

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DEPTOR, a novel endogenous inhibitor of mTOR, plays an important role in regulating the inflammatory response in vascular endothelial cells (ECs) and in mouse skeletal muscle. However, the regulatory mechanism of DEPTOR transcription and its effects on liver inflammation are unknown presently. Here we reported the role of DEPTOR in regulating inflammatory response in mouse liver-derived Hepa1-6 cells and in a mouse model with LPS-induced hepatic inflammation. The results revealed that DEPTOR over-expression in Hepa1-6 liver cells increased the mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). Contrasting results were observed in Hepa1-6 cells with DEPTOR interference. Treatment Hepa1-6 cells with rapamycin, a specific inhibitor of mTORC1, increased MCP-1 mRNA, but have no significant effect on IL-6 mRNA. DEPTOR expression was down-regulated in Hepa1-6 cells with the treatment of inflammatory stimuli LPS or the over-expression of p65/NF-κB, a key inflammatory transcription factor. NF-κB antagonist (PDTC) and inhibitor (IκBα) blocked the effect of LPS on DEPTOR expression. The study in vivo showed that DEPTOR mRNA and protein were significantly reduced in a mouse model with LPS-induced hepatic inflammation, which was accompanied by a concurrent activation of the mTOR signaling pathway. Further, the transcriptional regulation of DEPTOR was explored, which revealed that DEPTOR promoter activity was significantly down-regulated by NF-κB. The progressive deletions and mutations demonstrated that the NF-κB binding motif situated at -145/-127 region is an essential component required for the DEPTOR promoter activity. Chromatin immunoprecipitation (ChIP) assays determined that p65 can directly interact with the DEPTOR promoter DNA. Those results indicate DEPTOR regulates liver inflammation at least partially via mTORC1 pathway, and is down-regulated by LPS through p65.

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Section: Chromatin Immunoprecipitation (Chip) Assaysmentioning

confidence: 99%

p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes

Jin

et al. 2016

Gene

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“…Therefore, the identification of mechanisms underlying 11β-HSD1 activity may improve the understanding of the pathogenesis of certain diseases. Tumor necrosis factor-α (TNF-α) and IL-1β are associated with 11β-HSD1 activity, which are also key mediators in OA pathogenesis (9). The present study aimed to identify the signaling pathways involved in 11β-HSD1-mediated inflammatory responses by human OA fibroblast-like synoviocytes (FLSs) and to determine whether this process is inhibited by the use of a selective 11β-HSD inhibitor, BVT-2733.…”

Section: Introductionmentioning

confidence: 99%

Blockade of 11β-hydroxysteroid dehydrogenase type 1 enzyme inhibits experimental collagenase-induced osteoarthritis

Qiao

et al. 2014

Molecular Medicine Reports

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Abstract. Osteoarthritis (OA) is a common cause of functional deterioration in the joints of elderly adults and is a significant burden on the health of the aging population. 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts cortisone to cortisol, is known to contribute to a number of inflammatory diseases. However, the role of 11β-HSD1 in human OA remains unclear. The aim of this study was to identify the effects of the selective 11β-HSD1 inhibitor, BVT-2733, in murine collagenase-induced osteoarthritis (CIOA). CIOA mice were treated with BVT-2733 (100 mg/kg, orally) or control vehicle twice daily for five weeks. Cartilage and bone destruction were subsequently examined. The expression of bone markers and STAT3 phosphorylation in joint tissues were detected using western blot analysis. The concentrations of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay. Treatment with BVT-2733 attenuated cartilage and bone destruction, and reduced the expression of bone markers and p-STAT3 in the joints of CIOA mice. BVT-2733 also decreased the serum levels of interleukin (IL)-1β, IL-6, IL-17 and vascular endothelial growth factor. In conclusion, the present study showed that BVT-2733 inhibits multiple inflammatory signaling pathways in the joints of CIOA mice, suggesting that 11β-HSD1 inhibition may have therapeutic potential in human OA. IntroductionOsteoarthritis (OA) is a common cause of functional deterioration in the joints of older adults and confers a significant burden on the health of the elderly population (1). OA is characterized by the progressive destruction of cartilage. The current understanding of the molecular events during joint destruction suggests that activated synoviocytes are important in the pathogenesis of OA (2-3). Inflammatory mediators, including interleukin (IL)-1β, infiltrate the synovial membrane, resulting in further inflammation. (4). These mediators amplify and sustain the disease process in OA by inducing inflammatory mediators involved in cartilage degradation, such as matrix metalloproteinases (MMPs) (5). Thus, inflammatory mediator-activated pathways have received increasing attention as potential targets for the treatment of human OA in recent years.Endogenous glucocorticoid concentrations are determined by the activity of the hypothalamic-pituitary-adrenal axis, and tissue and intracellular exposure are further augmented through the activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts inactive cortisone to the active glucocorticoid, cortisol (6). The ability of 11β-HSD1 to elevate cellular glucocorticoid levels has been postulated to be involved in the modulation of a number of metabolic and inflammatory diseases (7,8). Therefore, the identification of mechanisms underlying 11β-HSD1 activity may improve the understanding of the pathogenesis of certain diseases. Tumor necrosis factor-α (TNF-α) and IL-1β are associated with 11β-HSD1 activity, which are also key mediators in OA pathogenesis (9)....

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“…NF-κB was reported to positively regulate HSD11B1 expression in human synovial fibroblasts and human dermal fibroblasts 31 and in adipocytes of diet-induced obese mice 32 . However, it was also shown to inhibit the expression of HSD11B1 in mouse skeletal muscle cells 33 . Our results with human UC-MSCs are consistent with those obtained with fibroblasts and adipocytes, which are presumably derived from MSCs.…”

Section: Discussionmentioning

confidence: 99%

HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs

Huang

et al. 2020

Cell Death Discov.

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Inflammatory factors such as IFNγ and TNFα could endow mesenchymal stem cells (MSCs) a potent immunomodulatory property, a process called licensing, but the mechanisms are not fully understood. We here found that glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to the active cortisol and thereby regulates tissue glucocorticoid (GC) levels, was greatly upregulated by IFNγ and TNFα in human umbilical cord-derived MSCs (UC-MSCs) in a synergistic manner. While IFNγ alone was not able to induce HSD11B1, it could increase the activity of NF-kB and thus augment the upregulation of HSD11B1 by TNFα. Interestingly, the upregulation of HSD11B1 by IFNγ and TNFα also required glucocorticoid receptor. Furthermore, HSD11B1 was shown to be required for the expression of TNF-stimulated gene 6 (TSG-6), an important anti-inflammatory effector molecule of MSCs. Therefore, the inflammatory factors IFNγ and TNFα can promote GC metabolism and thereby drive the expression of anti-inflammatory factor TSG-6 in human UC-MSCs, forming a potential negative feedback loop. These findings help to understand the relationship between inflammation and GC metabolism.

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TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

Cited by 7 publications

References 29 publications

p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes

p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes

Blockade of 11β-hydroxysteroid dehydrogenase type 1 enzyme inhibits experimental collagenase-induced osteoarthritis

HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs

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