Rapamycin attenuates BAFF‐extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B‐lymphoid cells

Zeng, Qingyu; Qin, Shanshan; Zhang, Hai; Liu, Beibei; Qin, Jiamin; Wang, Xiaoxue; Zhang, Ruijie; Liu, Chunxiao; Dong, Xiaoqing; Zhang, Shuangquan; Huang, Shile; Chen, Long

doi:10.1002/jcp.25913

Cited by 24 publications

(8 citation statements)

References 59 publications

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“…mTOR is a protein kinase that connects cellular metabolic processes with a wide range of environmental signals, such as proinflammatory cytokines, nutrients, and growth factors. The abnormal activation of mTOR drives the proinflammatory expansion of T helper (Th) type 1, 14 Th17, 15 , 16 and CD4–CD8– (double-negative, DN) T cells 17 and promotes B cell proliferation/survival 18 as well as the expansion of T-bet+CD11c+ atypical memory B cells, 19 but inhibits the development of CD4+CD25+FoxP3+ T regulatory (Treg) cells, 20 attributed to the pathogenesis of SLE and other autoimmune diseases. 21 – 26 In fact, numerous studies indeed have shown that mTOR activation precedes the onset and flare of SLE.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis

Peng

Hong

et al. 2020

Therapeutic Advances in Musculoskeletal

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Objective: To provide real-world data and summarize current clinical evidence on the efficacy and safety of sirolimus in active systemic lupus erythematosus (SLE) patients. Methods: This was a prospective real-world clinical study. Included SLE patients should have Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ⩾ 2. They were treated with sirolimus and followed up regularly. The SLEDAI-2K, Physician Global Assessment (PGA), serological activity indices, and remission of organ manifestations were evaluated. We also performed a meta-analysis to integrate current evidence of sirolimus in SLE. Results: A total of 49 patients were included in the final analysis. After treatment, the SLEDAI-2K (6.2 ± 3.1 versus 4.0 ± 3.4, p = 0.001) decreased significantly, and the prednisone dosage was tapered successfully (9.9 ± 8.8 mg/day versus 5.9 ± 4.0 mg/day, p = 0.002). Serological activity indices also improved [complement 3 (C3): 0.690 ± 0.209 g/l versus 0.884 ± 0.219 g/l, p < 0.001; complement 4: 0.105 ± 0.059 g/l versus 0.141 ± 0.069 g/l, p < 0.001; anti-dsDNA antibody, 200 ± 178 IU/ml versus 156 ± 163 IU/ml, p = 0.022]. The remission proportions of arthritis, skin rash, and thrombocytopenia were 100%, 88.8%, and 46.2%, respectively. A total of 41.2% of lupus nephritis (LN) patients achieved renal remission, but the average 24-h urine protein level was not significantly changed. Meta-analysis enrolled five studies with 149 patients included, and revealed similar results regarding the changes of SLEDAI-2K [−3.5 (−5.0, −2.1)], C3 [0.224 (0.136, 0.311) g/l] and daily dosage of prednisone [−12.7 (−19.9, −5.6) mg/day]. Conclusion: Sirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.

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Section: Discussionmentioning

confidence: 99%

Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis

Peng

Hong

et al. 2020

Therapeutic Advances in Musculoskeletal

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“…Recent studies have reported that rapamycin could block the phosphorylation of S6K1 and Akt in neuronal cells, and attenuate apoptotic cell death [34]. Moreover, Zeng et al [35] showed that rapamycin inhibited phosphorylation of S6K1 and Akt in B cells, indicating that rapamycin prevented B cell proliferation through both mTORC1 and mTORC2 pathways. Our study demonstrated that rapamycin blocked the IL-13-induced deficiency of epidermal barrier related proteins not only via targeting mTORC1-mediated S6K1 pathway, but also through mTORC2-mediated Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin blocks the IL-13-induced deficiency of Epidermal Barrier Related Proteins via upregulation of miR-143 in HaCaT Keratinocytes

Jia

2020

Int. J. Med. Sci.

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Interleukin (IL)-13 plays a key role in the pathogenesis of atopic dermatitis (AD). Our preliminary study demonstrated that forced expression of miR-143 could block IL-13-induced down-regulation of epidermal barrier related proteins in epidermal keratinocytes. As previous studies suggested that miR-143 expression was regulated by mammalian target of rapamycin (mTOR) signaling pathway, we investigated the mechanism of mTOR signaling pathway in the epidermal barrier dysfunction of AD. The HaCaT cells were stimulated by IL-13 and subsequently treated with rapamycin. The expression levels of miR-143, IL-13 receptor α1 (IL-13Rα1), p-mTOR, p-S6K1, p-Akt, and epidermal barrier related proteins were analyzed through RT-qPCR and/or western blotting. The current study showed that IL-13 increased the expression levels of p-mTOR, p-S6K1, and p-Akt, and that rapamycin blocked IL-13-induced down-regulation of miR-143, suppressed the IL-13Rα1 expression and up-regulated the expressions of filaggrin, loricrin, and involucrin in HaCaT cells. This study proposed that IL-13 could activate the mTOR signaling pathway, and confirmed the vital role of mTOR-miR-143 signaling axis in the pathogenesis of AD. It provided solid evidences regarding rapamycin as a potential effective therapeutic option in the management of AD.

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“…Furthermore, B cells from mice deficient for Rptor , an essential component of mTORC1,25 26 have distinguished loss of S6 phosphorylation at serine 235/236. Furthermore, phosphorylation of S6 at serine 235/236 is sensitive to rapamycin in B cell activating factor belonging to the TNF family (BAFF)-stimulated primary B cells13 indicating that S6 phosphorylation at serine 235/236 largely reflects mTOR pathway activation in B cells.…”

Section: Discussionmentioning

confidence: 99%

Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?

Blokland

Hillen

Wichers³

et al. 2019

RMD Open

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Rapamycin attenuates BAFF‐extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B‐lymphoid cells

Cited by 24 publications

References 59 publications

Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis

Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis

Rapamycin blocks the IL-13-induced deficiency of Epidermal Barrier Related Proteins via upregulation of miR-143 in HaCaT Keratinocytes

Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?

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