Dataset Information

Tripterygium Wilfordii inhibits tonsillar IgA production by downregulating IgA class switching in IgA nephropathy.

ABSTRACT: IgA nephropathy (IgAN) is characterized by high serum IgA levels and IgA deposition in the renal mesangium. Recent research has indicated that pathogenic IgA may originate from affected tonsils, where present enhancement of IgA production by IgA class switching and immuno-activation. Tripterygium Wilfordii (TW) was found to be especially effective in IgAN by its' immunosuppression effect. Given this background, we investigated the mechanisms underlying the role of TW in the generation of IgA and IgA class switching in tonsillar GCs of IgAN patients. Immunohistochemistry and RT-PCR revealed that the expression of thymic stromal lymphopoietin (TSLP) and IgA inducing cytokines were decreased in the tonsils of IgAN patients with TW treatment compared with those without treatment, followed by significantly decreased of IgA-bearing cells. The location of TSLP and IgA inducing cytokines in tonsillar tissue was confirmed by double immunofluorescence. Importantly, TW inhibit TSLP and IgA production in isolated FDC-associated clusters. Serum TSLP levels were decreased and correlated with IgA downregulation in the tonsils and serum of IgAN patients. These data indicated that TW may be involved in IgA production in the tonsils of IgAN patients, inhibiting IgA class switching in IgAN patients through the cooperative roles of AID, TGF-?1, BAFF, and APRIL, highlighting a promising strategy for therapeutic intervention in IgAN.

SUBMITTER: Li H

PROVIDER: S-EPMC5752501 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Tripterygium Wilfordii inhibits tonsillar IgA production by downregulating IgA class switching in IgA nephropathy.

Li Huining H Kong Dan D Xu Yangyang Y Li Xiaomei X Yao Guodong G Chen Kexin K You Qi Q Shi Qingtao Q Zhang Lei L Wang Xin X Yuan Dawei D Miao Shusheng S Geng Jingshu J Jin Xiaoming X Meng Hongxue H

Oncotarget 20171120 65

IgA nephropathy (IgAN) is characterized by high serum IgA levels and IgA deposition in the renal mesangium. Recent research has indicated that pathogenic IgA may originate from affected tonsils, where present enhancement of IgA production by IgA class switching and immuno-activation. Tripterygium Wilfordii (TW) was found to be especially effective in IgAN by its' immunosuppression effect. Given this background, we investigated the mechanisms underlying the role of TW in the generation of IgA and ...[more]

PMID: 29312588

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Project description:Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease and poses a global major public health burden. The preparation of Tripterygium wilfordii Hook F (TwHF) is widely applied for treating patients with Immunoglobulin A nephropathy in China, while the molecular mechanisms remain unclear. This study aimed to verify the therapeutic mechanism of TwHF on IgAN by undertaking a holistic network pharmacology strategy in combination with in vitro and in vivo experiments. Methods: TwHF active ingredients and their targets were obtained via the Traditional Chinese Medicine Systems Pharmacology Database. The collection of IgAN-related target genes was collected from GeneCards and OMIM. TwHF-IgAN common targets were integrated and visualized by Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the predominant molecular mechanisms and pathways of TwHF on the treatment of IgAN. The protein-protein interaction network was constructed by the STRING online search tool, and hub genes were identified using R software. The expression of hub gene and related signaling were evaluated in TwHF-treated mice through immunohistochemistry and western blot and further validated in human mesangial cells (HMCs). In addition, Cell counting kit 8 (CCK8) and flow cytometry were used to detect the effects of TwHF on cell proliferation and cell cycle of mesangial cells. Results: A total of 51 active ingredients were screened from TwHF and 61 overlapping targets related to IgAN were considered potential therapeutic targets, GO functions and KEGG analyses demonstrated that these genes were primarily associated with DNA-binding transcription factor binding, lipid and atherosclerosis pathway. Genes with higher degrees including AKT1, CXCL8, MMP9, PTGS2, CASP3, JUN are hub genes of TwHF against IgAN. Verification of hub gene JUN both in vitro and in vivo showed that TwHF significantly attenuated JUN phosphorylation in the kidneys of IgAN mice and aIgA1-activated HMCs, meanwhile suppressing HMCs proliferation and arresting G1-S cell cycle progression. Conclusion: Our research strengthened the mechanisms of TwHF in treating IgAN, inhibition of JUN activation may play a pivotal role in TwHF in alleviating IgAN renal injury.

Project description:BackgroundDiabetic nephropathy (DN) is the most common cause of end-stage renal failure. Although angiotensin II receptor blockers (ARBs) can be used to attenuate proteinuria in DN patients, their efficacy remains limited. This clinical trial aimed to evaluate the efficacy of Tripterygium wilfordii Hook F (TwHF) extract in the treatment of type 2 diabetes mellitus (DM)-induced nephropathy.MethodsA total of 65 DN patients with proteinuria levels ≥ 2.5 g/24 h and serum creatinine levels<3 mg/dl were enrolled in this six-month, prospective, randomized, controlled study. The patients were randomized into treatment groups that received either 120 mg of TwHF extract per day for three months, followed by 60 mg per day for three more months, or 160 mg of valsartan daily for six months. The urinary protein and estimated glomerular filtration (eGFR) level were measured at one, three, and six months after the commencement of treatment. The primary measure of treatment efficacy was a reduction in the 24-h urine protein level between baseline and the end of the study, and the secondary measure of treatment efficacy was a reduction in the eGFR value.ResultsAt the end of the treatment period, the mean urine protein level in the TwHF group was dramatically decreased (4.99 ± 2.25 g/24 h vs 2.99 ± 1.81 g/24 h, p< 0.01), with decreases at one, three, and six months of 32.9%, 38.8%, and 34.3%, respectively. In contrast, the proteinuria in the valsartan group was not significantly attenuated, and the decreases in urine protein levels at treatment months one, three, and six were 1.05%, 10.1%, and -11.7%, respectively. The mean decrease in eGFR in the valsartan group was greater than that in the TwHF group (26.4% vs. 13.7%, respectively; p =0.067).ConclusionsTwHF extract can reduce the urine protein level of DN patients and represents a novel, potentially effective, and safe drug for the treatment of DN patients with proteinuria.Trial registrationClinicalTrials.gov: NCT00518362.

Dataset Information

Tripterygium Wilfordii inhibits tonsillar IgA production by downregulating IgA class switching in IgA nephropathy.

Publications

Tripterygium Wilfordii inhibits tonsillar IgA production by downregulating IgA class switching in IgA nephropathy.

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