scholarly journals The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy

2020 ◽  
Vol 33 (6) ◽  
pp. 1251-1261 ◽  
Author(s):  
Junjun Zhang ◽  
Yiming Mi ◽  
Ruwen Zhou ◽  
Zhangsuo Liu ◽  
Bo Huang ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Mesangial Cells ◽  
Immunofluorescence Assay ◽  
Kidney Damage ◽  
Secretory Iga ◽  
Tnf Α ◽  
Mesangial Area ◽  
Enhanced Expression ◽  
Better Than

AbstractPrevious studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.

scholarly journals Sialylation of IgG inhibits the formation of galactose-deficient IgA1-containing immune complexes and protects mesangial cells from injury in IgA nephropathy

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Youxia Liu ◽  
Hongfen Li ◽  
Huyan Yu ◽  
Fanghao Wang ◽  
Junya Jia ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
B Lymphocytes ◽  
Immune Complexes ◽  
Mononuclear Cells ◽  
Mesangial Cells ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Inflammatory State

Abstract Background The addition of sialic acid alters IgG from a pro-inflammatory state to an anti-inflammatory state. However, there is a lack of research on the changes of IgG sialylation in IgA nephropathy (IgAN). Methods This study included a total of 184 IgAN patients. The sialylated IgG (SA-IgG), IgG-galactose-deficient IgA1 complex (IgG-Gd-IgA1-IC), IL-6, TNF-α, and TGF-β were detected using commercial ELISA kits. SA-IgG, non-sialylated IgG (NSA-IgG), sialylated IgG-IgA1 complex (SA-IgG-IgA1), and non-sialylated IgG-IgA1 complex (NSA-IgG-IgA1) were purified from IgAN patients and healthy controls (HCs). Results The mean SA-IgG levels in plasma and B lymphocytes in IgAN patients were significantly higher than those of healthy controls. A positive correlation was found between SA-IgG levels in plasma and B lymphocytes. In vitro, the results showed that the release of IgG-Gd-IgA1-IC was significantly decreased in peripheral blood mononuclear cells (PBMCs) cultured with SA-IgG from both IgAN patients and healthy controls. The proliferation ability and the release of IL-6, TNF-α, and TGF-β in human mesangial cells (HMCs) were measured after stimulating with SA-IgG-IgA1-IC and NSA-IgG-IgA1-IC. The mesangial cell proliferation levels induced by NSA-IgG-IgA1-IC derived from IgAN patients were significantly higher than those caused by SA-IgG-IgA1-IC derived from IgAN patients and healthy controls. Compared with NSA-IgG-IgA1 from healthy controls, IgAN-NSA-IgG-IgA1 could significantly upregulate the expression of IL-6 and TNF-α in mesangial cells. The data showed that there weren’t any significant differences in the levels of IL-6, TNF-α, and TGF-β when treated with IgAN-SA-IgG-IgA1 and HC-NSA-IgG-IgA1. Conclusions The present study demonstrated that the sialylation of IgG increased in patients with IgA nephropathy. It exerted an inhibitory effect on the formation of Gd-IgA1-containing immune complexes in PBMCs and the proliferation and inflammation activation in mesangial cells.

Activation of podocytes by mesangial-derived TNF-α: glomerulo-podocytic communication in IgA nephropathy

2008 ◽  
Vol 294 (4) ◽  
pp. F945-F955 ◽  
Author(s):  
Kar Neng Lai ◽  
Joseph C. K. Leung ◽  
Loretta Y. Y. Chan ◽  
Moin A. Saleem ◽  
Peter W. Mathieson ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Neutralizing Antibody ◽  
Important Mediator ◽  
Tnf Α ◽  
Strategic Position ◽  
Inflammatory Changes

We have previously documented that human mesangial cell (HMC)-derived TNF-α is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the role of mesangial cells in the activation of podocytes in IgAN. There was no binding of IgA from patients with IgAN to podocytes. Podocytes cultured with IgA from patients with IgAN did not induce the release of growth factors or cytokines. Furthermore, podocytes did not express mRNA of known IgA receptors. In contrast, IgA-conditioned medium (IgA-HMC medium) prepared by culturing HMC with IgA from patients with IgAN for 48 h significantly increased the gene expression and protein synthesis of TNF-α by podocytes with a 17-fold concentration above that of IgA-HMC medium. The upregulation of TNF-α expression by podocyte was only abolished by a neutralizing antibody against TNF-α but not by other antibodies. Exogenous TNF-α upregulated the synthesis of TNF-α by podocytes in an autocrine fashion. IgA-HMC medium prepared with IgA from patients with IgAN also significantly upregulated the expression of both TNF-α receptor 1 and 2 in podocytes. Our in vitro finding suggests podocytes may play a contributory role in the development of interstitial damage in IgAN by amplifying the activation of tubular epithelial cells with enhanced TNF-α synthesis after inflammatory changes of HMC.

Mass spectrometry-based circulating IgA1 complexes screening driven identification of IgA-alpha-1-microglobulin complex in IgA nephropathy

2020 ◽  
Author(s):  
Boyang Xu ◽  
Li Zhu ◽  
Qingsong Wang ◽  
Yanfeng Zhao ◽  
Meng Jia ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Iga Nephropathy ◽  
Cell Injury ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Independent Population ◽  
Tubulointerstitial Lesions ◽  
Noninvasive Biomarker

Abstract Background IgA nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls, and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Taken together the proteins content and injury effects, the key constituent in CICs was identified. Then, the circulating levels of identified key constituent-IgA complex were detected in an independent population by an in-house-developed ELISA. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, alpha-1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and MCP-1 secretion but also in vivo eGFR levels and tubulointerstitial lesions in IgAN patients. Moreover, we found alpha-1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, an elevated circulating IgA-alpha-1-microglobulin complex levels were detected in an independent IgAN population, and IgA-alpha-1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford-T scores in these IgAN patients. Conclusions Our results suggest that the IgA-alpha-1-microglobulin complex is an important constituent in CICs, and that circulating IgA-alpha-1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

In Silico Screening Anticancer of Six Triterpenoids toward miR-494 and TNF-α Targets

2020 ◽  
Vol 23 (4) ◽  
pp. 117-123
Author(s):  
Vikra Ardiansyah Zaini ◽  
Purwantiningsih Sugita ◽  
Luthfan Irfana ◽  
Suminar Setiati Achmadi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Ganoderma Lucidum ◽  
Inadequate Response ◽  
In Vitro Experiments ◽  
In Silico Screening ◽  
Lipinski’S Rule ◽  
Tnf Α ◽  
Liver Cancers ◽  
Better Than

Hepatocellular carcinoma (HCC) accounts for up to 90% of all primary liver cancers worldwide. Cinobufagin is recognized to inhibit miR-494 as the HCC target. Increased expression of TNF-α results in an inadequate response to liver anticancer drugs. The models in this study were cinobufagin, cycloartenol, and ethyl acetate fractions of Ganoderma lucidum, 2–5. Seven docking targets in this study were Akt, ERK1, ERK2, PI3K, TNF-α, TNFR1, and TNFR2. Cycloartenol and compound 4 comply with Veber’s rules, Lipinski’s rule of 5, and demonstrate moderate toxicity. The action implies a potential docking target since it produces bond affinities with the compound 2–5 that agree with the IC50 in the literature, which is based on in vitro experiments. Akt as a receptor target is AZD5363. Cycloartenol shows a low ability to inhibit Akt. Conversely, compound 4 inhibits the Akt better than that of cycloartenol, although it is not as good as cinobufagin and AZD5363. Therefore, compound 4, a triterpenoid with a basic framework of lanostane has the potential to be an anticancer candidate for the liver.

scholarly journals Proliferation and Cytokine Production of Human Mesangial Cells Stimulated by Secretory IgA Isolated from Patients with IgA Nephropathy

2015 ◽  
Vol 36 (5) ◽  
pp. 1793-1808 ◽  
Author(s):  
Yan Liang ◽  
Junjun Zhang ◽  
Yali Zhou ◽  
Guolan Xing ◽  
Guoqiang Zhao ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Biological Effects ◽  
Transforming Growth Factor Β1 ◽  
Secretory Iga ◽  
Serum Cystatin C ◽  
Serum Cystatin ◽  
Chemotactic Protein ◽  
The Oxford Classification

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and often aggravates by mucosal infection. Secretory IgA (SIgA) is the dominant immunoglobulin in mucosal immunity, and is deposited in the mesangium in IgAN. The biological effects of SIgA on mesangial cells are poorly understood. Methods: Deposition of SIgA in frozen renal sections from IgAN patients was detected and the association between deposition of SIgA and patients characteristics was analyzed. The biological effects of SIgA and polymeric IgA (pIgA) on human renal mesangial cells were compared. We also studied the molecular mechanism of microRNA regulating the inflammatory effects of SIgA on mesangial cells. Results: Fifty-five of 176 patients had SIgA deposition with higher incidence of infection history and hematuria, lower serum cystatin C, β2 microglobulin, blood urea nitrogen and T-grade in the Oxford classification, compared with patients without SIgA deposition. SIgA stimulated mesangial cells at a higher ratio of proliferation and higher production of interleukin (IL)-6, IL-8, monocyte chemotactic protein 1, transforming growth factor-β1 and fibronectin, compared with SIgA from healthy volunteers. The proliferation and cytokines production in mesangial cells stimulated by SIgA were significantly lower than that stimulated by pIgA. miR-16 targeted the 3′-untranslated region of IL-6 and suppressed its translation in mesangial cells induced by SIgA. Conclusions: The biological effects of SIgA on mesangial cells differ from those of pIgA. SIgA stimulates mesangial cell proliferation and production of proinflammatory cytokines. IL-6 production is regulated by miR-16 in mesangial cells.

MiR-100-3p and miR-877-3p regulate overproduction of IL-8 and IL-1β in mesangial cells activated by secretory IgA from IgA nephropathy patients

2016 ◽  
Vol 347 (2) ◽  
pp. 312-321 ◽  
Author(s):  
Yan Liang ◽  
Guoqiang Zhao ◽  
Lin Tang ◽  
Junjun Zhang ◽  
Tianfang Li ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Mesangial Cells ◽  
Secretory Iga

Collectin11 and Complement Activation in IgA Nephropathy

2021 ◽  
pp. CJN.04300321
Author(s):  
Min Wei ◽  
Wei-yi Guo ◽  
Bo-yang Xu ◽  
Su-fang Shi ◽  
Li-jun Liu ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Complement Activation ◽  
Immune Complexes ◽  
Mesangial Cells ◽  
Kidney Injury ◽  
Lectin Pathway ◽  
Independent Manner ◽  
Proximity Ligation ◽  
Injury Model

Background and objectives: IgA nephropathy is the most common primary glomerulonephritis worldwide. Previous research demonstrated that collectin11, an initiator of complement lectin pathway, was involved in both acute kidney injury and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. Design, setting, participants, and measurements: The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by RT-qPCR and immunofluorescence. The codeposition of collctin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. Results: 37% participants with IgA nephropathy (22/60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. Conclusions: In situ-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

scholarly journals Macromolecular IgA1 taken from patients with familial IgA Nephropathy or their asymptomatic relatives have higher reactivity to mesangial cells in vitro

2009 ◽  
Vol 75 (12) ◽  
pp. 1330-1339 ◽  
Author(s):  
Ka Ying Tam ◽  
Joseph C.K. Leung ◽  
Loretta Y.Y. Chan ◽  
Man Fai Lam ◽  
Sydney C.W. Tang ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Mesangial Cells

scholarly journals MCPIP1 Enhances TNF-α-Mediated Apoptosis through Downregulation of the NF-κB/cFLIP Axis

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 655
Author(s):  
Fat-Moon Suk ◽  
Chi-Ching Chang ◽  
Pei-Chi Sun ◽  
Wei-Ting Ke ◽  
Chia-Chen Chung ◽  
...  
Keyword(s):  
Immunofluorescence Assay ◽  
Caspase Inhibitor ◽  
Recognition Sequence ◽  
Apoptotic Pathway ◽  
Monocyte Chemoattractant Protein 1 ◽  
Caspase 1 ◽  
Iκb Kinase ◽  
293 Cells ◽  
Tnf Α

Monocyte chemoattractant protein-1-induced protein 1 (MCPIP1) is rapidly produced under proinflammatory stimuli, thereby feeding back to downregulate excessive inflammation. In this study, we used the stable, inducible expressions of wild-type (WT) MCPIP1 and an MCPIP1-D141N mutant in T-REx-293 cells by means of a tetracycline on (Tet-on) system. We found that WT MCPIP1 but not MCPIP1-D141N mutant expression dramatically increased apoptosis, caspase-3, -7, -8, and -9 activation, and c-Jun N-terminal kinase (JNK) phosphorylation in TNF-α-treated cells. The pan-caspase inhibitor, z-VAD-fmk, and the caspase-1 inhibitor, z-YVAD-fmk, but not the JNK inhibitor, SP600125, significantly reversed apoptosis and caspase activation in TNF-α/MCPIP1-treated cells. Surprisingly, MCPIP1 itself was also cleaved, and the cleavage was suppressed by treatment with the pan-caspase inhibitor and caspase-1 inhibitor. Moreover, MCPIP1 was found to contain a caspase-1/-4 consensus recognition sequence located in residues 234~238. As expected, the WT MCPIP1 but not the MCPIP1-D141N mutant suppressed NF-κB activation, as evidenced by inhibition of IκB kinase (IKK) phosphorylation and IκB degradation using Western blotting, IKK activity using in vitro kinase activity, and NF-κB translocation to nuclei using an immunofluorescence assay. Interestingly, MCPIP1 also significantly inhibited importin α3 and importin α4 expressions, which are major nuclear transporter receptors for NF-κB. Inhibition of NF-κB activation further downregulated expression of the caspase-8 inhibitor, cFLIP. In summary, the results suggest that MCPIP1 could enhance the TNF-α-induced apoptotic pathway through decreasing NF-κB activation and cFLIP expression.

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