肿瘤坏死因子受体相关因子6与凋亡关系的研究进展

目的总结肿瘤坏死因子受体相关因子6（TRAF6）与凋亡的关系。方法通过检索国内外相关文献,总结TRAF6在调节凋亡信号通路中的角色及其在相关疾病发生和发展过程中的作用。结果 TRAF6通过参与多条信号传导通路调节凋亡,在不同的组织器官及不同的刺激下对调节凋亡发挥不同的作用。TRAF6通过抑制凋亡促进肿瘤发生,而在神经系统和炎症相关疾病中则发挥促凋亡或促存活作用。结论 TRAF6通过调节凋亡,在肿瘤、神经系统及炎症相关疾病的发生和发展中均扮演了重要的角色。     

血液透析患者骨密度与骨保护素和核因子κB受体 活化因子配体的关系

核因子κB受体活化因子配体(RANKL)是近年来在肿瘤坏死因子配体超家族中发现的一种具有调控破骨细胞产生和活化作用的细胞因子[1].它与骨保护素(OPG)、核因子κB受体活化因子(RANK)的相互作用,能调节破骨细胞的活化和增殖,维持正常骨重建过程.     

肺高血压大鼠肺组织肿瘤坏死因子受体相关因子6表达的变化

目的明确肺高血压(PH)大鼠肺组织肿瘤坏死因子受体相关因子6(TRAF6)表达的变化。方法 SPF级健康雄性SD大鼠16只, 8周龄, 体质量200～220 g, 采用随机数字表法分为2组(n=8):对照组(C1组)和PH1组。采用皮下注射野百合碱的方法制备大鼠PH模型。模型制备开始后28 d时, 测量大鼠平均肺动脉压力(mPAP), 计算Fulton指数, 计算肺中小动脉中膜厚度百分比, 计算肌化血管百分比, Western blot法检测肺组织TRAF6、信号转导和转录激活因子3(STAT3)、磷酸化信号转导和转录激活因子(p-STAT3)和G1/S-特异性周期蛋白-D1(Cyclin D1)表达, 计算p-STAT3/STAT3, 免疫共沉淀法检测TRAF6与STAT3的相互作用。原代培养正常大鼠肺动脉平滑肌细胞(C2组)和PH大鼠肺动脉平滑肌细胞(PH2组)于6孔板(n=3)。采用qPCR法检测TRAF6 mRNA表达, Western blot法检测TRAF6、STAT3、p-STAT3和Cyclin D1表达。结果与C1组比较, PH1组大鼠mPAP、Fulton指数、肺中...     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

肿瘤坏死因子受体相关因子6在小鼠急性胰腺炎中的定量表达

急性胰腺炎(AP)的发病机制尤其是分子机制不清楚.研究显示Toll样受体4(TLR4)在AP的发病过程中起重要的作用[1].我们采用雨蛙素诱导AP模型,探讨AP过程中,肿瘤坏死因子受体相关因子6(TRAF6)和TLR4的作用.     

Identification and characterization of anti-osteoclastogenic peptides derived from the cytoplasmic tail of receptor activator of nuclear factor kappa B

Pathological bone resorption by osteoclasts is primarily treated with bisphosphonates. Because the administration of bisphosphonates is associated with a risk for multiple adverse symptoms, a precise understanding of the mechanisms underlying osteoclastogenesis is required to develop drugs with minimal side-effects. Osteoclastogenesis depends on receptor activator of nuclear factor kappa B (RANK) signaling mediated by TRAF6. We previously identified a highly conserved domain in the cytoplasmic tail of RANK (HCR), which did not share any significant homology with other proteins and was essential for osteoclastogenesis. HCR acts as a platform for the formation of Gab2- and Vav3-containing signal complexes, and ectopic expression of the HCR peptide inhibits osteoclastogenesis. Here, we uncover the mechanisms of HCR peptide-mediated inhibition of osteoclastogenesis. Expression of either the amino- or carboxyl-terminal half of the HCR peptide (N- or C-peptide) independently inhibited RANK signaling prior to cell-cell fusion. In contrast, expression of the GY-peptide, which is a part of the C-peptide, did not significantly affect prefusion RANK signaling, but did inhibit cell-cell fusion to prevent formation of multinucleated mature osteoclasts. Moreover, Gab2, which is involved in RANK signaling by binding TRAF6, bound the C-peptide but not the N-peptide, suggesting that the C- and the N-peptides sequester TRAF6 in a Gab2-dependent and Gab2-independent manner, respectively. In contrast, the GY-peptide did not bind Gab2 but could bind Vav3, which mediates signaling for cell-cell fusion. Collectively, we propose that the HCR peptide inhibits osteoclastogenesis through two modes of action-inhibition of (1) prefusion RANK signaling and (2) cell-cell fusion by blocking TRAF6- and Vav3-mediated signaling, respectively.     

Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6.

Although tumor necrosis factor receptor-associated factor 6 (TRAF6) is required in receptor activator of NF-kappaB-receptor activator of NF-kappaB ligand (RANK-RANKL) signaling for osteoclastogenesis, it has remained unclear whether TRAF6 is crucial in tumor necrosis factor alpha (TNF-alpha)-induced osteoclastogenesis. We examined TRAF6 function in the TNF-alpha-induced osteoclastogenesis by using osteoclast progenitor cells from TRAF6-deficient mice. The results indicated that TNF-alpha did not effectively induce osteoclast differentiation from osteoclast progenitor cells derived from these mice into mature multinucleated osteoclasts, although c-jun N-terminal kinase (JNK) and TNF-alpha activation was observed in osteoclast progenitor cells. Thus, we have provided the first evidence showing that TRAF6 is involved in TNF-alpha-induced osteoclastogenesis.     

IL-6 signaling blockade increases inflammation but does not improve muscle function in the mdx mouse

ABSTRACT: BACKGROUND: IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx) of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse. Methods: A monoclonal antibody against the IL-6 receptor (IL-6r mAb) that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined. Results: IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength or muscle pathology due to IL-6r mAb treatment in mdx mice. Conclusions: These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.     

Interleukin-11 receptor signaling is required for normal bone remodeling.

IL-6 and -11 regulate bone turnover and have been implicated in estrogen deficiency-related bone loss. In this study, deletion of IL-11 signaling, but not that of IL-6, suppressed osteoclast differentiation, resulting in high trabecular bone volume and reduced bone formation. Furthermore, IL-11 signaling was not required for the effects of estradiol or estrogen deficiency on the mouse skeleton. INTRODUCTION: Interleukin (IL)-6 and -11 stimulate osteoclastogenesis and bone formation in vitro and have been implicated in bone loss in estrogen deficiency. Because of their common use of the gp130 co-receptor signaling subunit, the roles of these two cytokines are linked, and each may compensate for the absence of the other to maintain trabecular bone volume and bone cell differentiation. MATERIALS AND METHODS: To determine the interactions in bone between IL-11 and IL-6 in vivo and whether IL-11 is required for normal bone turnover, we examined the bone phenotype of mature male and female IL-11 receptor knockout mice (IL-11Ralpha1-/-) and compared with the bone phenotype of IL-6-/- mice and mice lacking both IL-6 and IL-11Ralpha. To determine whether IL-11 is required for the effects of estrogen on trabecular bone, mature IL-11Ralpha1-/- mice were ovariectomized and treated with estradiol. RESULTS: In both male and female IL-11Ralpha1-/- mice, trabecular bone volume was significantly higher than that of wildtype controls. This was associated with low bone resorption and low bone formation, and the low osteoclast number generated by IL-11Ralpha1-/- precursors was reproduced in ex vivo cultures, whereas elevated osteoblast generation was not. Neither trabecular bone volume nor bone turnover was altered in IL-6-/- mice, and compound IL-6-/- :IL-11Ralpha1-/- mice showed an identical bone phenotype to IL-11Ralpha1-/- mice. The responses of IL-11Ralpha1-/- mice to ovariectomy and estradiol treatment were the same as those observed in wildtype mice. CONCLUSIONS: IL-11 signaling is clearly required for normal bone turnover and normal trabecular bone mass, yet not for the effects of estradiol or estrogen deficiency on the skeleton. In the absence of IL-11Ralpha, increased trabecular bone mass seems to result from a cell lineage-autonomous reduction in osteoclast differentiation, suggesting a direct effect of IL-11 on osteoclast precursors. The effects of IL-11Ralpha deletion on the skeleton are not mediated or compensated for by changes in IL-6 signaling.     

Regulation of RANKL‐induced osteoclastogenesis by TGF‐β through molecular interaction between Smad3 and Traf6

Previous studies have shown that transforming growth factor β (TGF‐β) promotes receptor activator of nuclear factor‐κB ligand (RANKL)–induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF‐β signals were blocked either by a specific inhibitor of TGF‐β type 1 receptor kinase activity, SB431542, or by introducing a dominant‐negative mutant of TGF‐β type 2 receptor, RANKL‐induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c‐Ski markedly suppressed RANKL‐induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6‐TAB1‐TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6‐TAB1‐TAK1 complex formation was not observed when TGF‐β signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6‐TAB1‐TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKL‐induced osteoclast differentiation. In summary, TGF‐β is indispensable in RANKL‐induced osteoclastogenesis, and the binding of Smad3 to the TRAF6‐TAB1‐TAK1 complex is crucial for RANKL‐induced osteoclastogenic signaling. © 2011 American Society for Bone and Mineral Research.     

Regulation of RANKL‐induced osteoclastogenesis by RING finger protein RNF114

Normal bone remodeling is a continuous process orchestrated by bone‐resorbing osteoclasts and bone‐forming osteoblasts, which an imbalance in bone remodeling results in metabolic bone diseases. RANKL, a member of the TNF cytokine family, functions as a key stimulator for osteoclast differentiation and maturation. Here, we report that RNF114, previously identified as a psoriasis susceptibility gene, plays a regulatory role in the RANKL/RANK/TRAF6 signaling pathway that mediates osteoclastogenesis. Our results demonstrated that RNF114 expression was significantly down‐regulated in mouse osteoclast precursor cells undergoing RANKL‐induced osteoclast differentiation. RNF114 knockout did not affect development or viability of the subpopulation of bone marrow macrophages capable of differentiating into osteoclasts in culture. However, in the presence of RANKL, RNF114 knockout bone marrow macrophages exhibited enhanced cell proliferation and augmented osteoclast differentiation, as shown by an increased expression of mature osteoclast markers, increased osteoclastic TRAP activity and bone resorption. Conversely, ectopic expression of RNF114 inhibited CTSK expression, TRAP activity, and bone resorption in RANKL‐treated pre‐osteoclasts. RNF114 also suppressed RANKL‐activated NFATc1 expression and NFAT‐regulated promoter activity. RNF114 suppressed TRAF6‐, but not TAK1/TAB2‐mediated NF‐κB activation downstream of RANKL/RANK. In particular, TRAF6 protein levels were down‐regulated by RNF114, possibly via K48‐mediated proteasome‐dependent degradation. These data suggested that RNF114's inhibitory effect on RANKL‐stimulated osteoclastogenesis was mediated by blocking RANK/TRAF6/NF‐κB signal transduction. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:159–166, 2018.