Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

Zhou, Guangxi; Wu, Wei; Lin, Yu; Yu, Tianxiang; Yang, Wenjing; Wang, Ping; Zhang, Xiaoping; Cong, Yingzi; Liu, Zhanju

doi:10.1016/j.jaci.2017.09.038

Cited by 48 publications

(29 citation statements)

References 49 publications

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“…IFN-γ-producing Th1 cells, IL-4-producing Th2 cells, IL-17A-producing Th17 cells, and Treg cells are reported to be essential for intestinal mucosal homeostasis in the pathogenesis of UC [13,38]. Our published data have demonstrated that Tripartite motif-containing (TRIM) 21 and Rho-associated kinase 2 influenced IBD CD4 + T cells to differentiate into Th1, Th17 and Treg cells [14,15]. Therefore, we wondered whether LRCH1 participated in the pathogenesis of UC through modulating the differentiation of CD4 + T cells.…”

Section: Discussionmentioning

confidence: 91%

“…International Publisher pathways, naïve CD4 + T cells differentiated into helper T (Th) cells, termed Th1, Th2 and Th17, and induced regulatory T cells (Treg), which suppressed the effector functions of other types of Th cell [13]. Our previous studies have demonstrated that abnormal Th1 and Th17 immune responses promoted colonic mucosal inflammation, whereas Treg cells possessed the suppressive activity, characterized by high levels of IL-10 and TGF-β [14,15]. It is reported that Th1 cells were highly enriched in the inflamed mucosa of IBD patients, and downregulation of CXCR3 in Th1 cells interfered with the migration of Th1 cells into the colonic mucosa and protected mice against severe acute and relapsing intestinal inflammation [16].…”

Section: Ivyspringmentioning

confidence: 99%

“…Peripheral blood CD4 + T cells were isolated by using anti-human CD4 particles and activated with plate-bound anti-CD3 (5 mg/mL) and anti-CD28 (2 mg/mL) mAbs for 48 h [15]. These cells (1×10 5 /well) were transfected with lentivirus-expressing LRCH1 (LV-LRCH1, ID: NM_015116.2) or LV-sh-LRCH1 (target sequence: 5'-GCAGATAGGTCAGTTGAAA TC-3') or with either negative control lentiviral vector (LV-NC) according to the manufacturer's protocols (multiplicity of infection = 180, Biolink, Shanghai, China).…”

Section: Lentivirus-mediated Cd4 + T-cell Transfectionmentioning

confidence: 99%

“…After 3 washes with RPMI 1640 medium, transfected cells were resuspended in complete RPMI 1640 medium and then cultured for 5 days. During this period, transfection efficiency was assessed by means of fluorescent microscopy 72 h after transfection [15]. These CD4 + T cells were harvested for flow cytometry analysis and qRT-PCR.…”

Section: Lentivirus-mediated Cd4 + T-cell Transfectionmentioning

confidence: 99%

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LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

Wang¹,

Zhang²,

He³

et al. 2020

Int. J. Med. Sci.

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Background: Ulcerative colitis (UC) is a chronically remittent and progressive inflammatory disorder. LRCH1 is reported to be involved in the immune-regulation of several diseases. However, the exact roles of LRCH1 in UC are still obscure. Materials and Methods: LRCH1 expression was analyzed in the inflamed mucosa and peripheral blood mononuclear cells (PBMCs) from patients with UC by quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4 + T cells were transfected with lentivirus-expressing LRCH1 (LV-LRCH1) or LV-sh-LRCH1, and cytokine expression was determined by using flow cytometry, quantitative RT-PCR and ELISA. Transfected CD4 + T cells were harvested to examine the capacity of chemotaxis using Transwell plate. Results: LRCH1 expression was highly decreased in colonic mucosa and PBMCs from patients with A-UC, and negatively correlated with disease activity. Up or down regulation of LRCH1 did not affect the differentiation of CD4 + T cells, and the related cytokines expression. Moreover, LRCH1 inhibited migratory capacity of CD4 + T cells toward CXCL12 by PKCα. Conclusion: LRCH1 plays an important role in the pathogenesis of UC, possibly through modulating the migration of CD4 + T cells. Therefore, targeting LRCH1 might serve as a novel therapeutic approach in the management of UC.

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Section: Discussionmentioning

confidence: 91%

Section: Ivyspringmentioning

confidence: 99%

Section: Lentivirus-mediated Cd4 + T-cell Transfectionmentioning

confidence: 99%

Section: Lentivirus-mediated Cd4 + T-cell Transfectionmentioning

confidence: 99%

See 2 more Smart Citations

LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

Wang¹,

Zhang²,

He³

et al. 2020

Int. J. Med. Sci.

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“…TRIM21 has been associated with the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus (SLE) and inflammatory bowel diseases (IBDs). TRIM21 plays a protective role in IBD pathogenesis, possibly through inhibition of Th1 and Th17 cell immune responses in the intestinal mucosa [45] – [47]. In view of the detected interaction, it is possible that pathways involving CIP2A are also active in the pathogenesis of autoimmune diseases like SLE and IBD.…”

Section: Discussionmentioning

confidence: 99%

Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells

Khan

Välikangas

Khan

et al. 2019

Preprint

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29Cancerous inhibitor of protein phosphatase 2A (CIP2A) is involved in immune 30 response, cancer progression, and in Alzheimer´s disease. However, an 31 understanding of the mechanistic basis of its function in this wide spectrum of 32 physiological and pathological processes is limited due to its poorly characterized 33 interaction networks. Here we present the first systematic characterization of the 34 CIP2A interactome by affinity-purification mass spectrometry combined with validation 35 by selected reaction monitoring targeted mass spectrometry (SRM-MS) analysis in 36 Th17 cells. In addition to the known regulatory subunit of protein phosphatase PP2A, 37 the catalytic subunit of protein PP2A was found to be interacting with CIP2A. 38 Furthermore, the regulatory (PPP1R18, and PPP1R12A) and catalytic (PPP1CA) 39 subunits of phosphatase PP1 were identified among the top novel CIP2A interactors. 40 Evaluation of the ontologies associated with the proteins in this interactome revealed 41 that they were linked with RNA metabolic processing and splicing, protein traffic, 42 cytoskeleton regulation and ubiquitin-mediated protein degradation processes. Taken 43 together, this network of protein-protein interactions will be important for 44 understanding and further exploring the biological processes and mechanisms 45 regulated by CIP2A both in physiological and pathological conditions.46 Monitoring (SRM) targeted mass spectrometry, confocal microscopy, Pathway 48 analysis.49 Highlights: 50 § The first characterisation of the CIP2A interactome in Th17 cells. 51 3 § Key interactions were validated by targeted SRM-MS proteomics, western blot 52 and confocal microscopy. 53 § Pathway analysis of the interactome revealed interrelationships with proteins 54 across a broad range of processes, in particular associated with mRNA 55 processing. 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72PP2A is a recognized tumor suppressor that imparts crucial functions in regulating cell 73 proliferation, differentiation, and apoptosis [1] - [7] . Accordingly, down regulation of 74 PP2A has been observed as a feature in many cancers. Cancerous Inhibitor of PP2A 75 (CIP2A) was first characterized as an endogenous inhibitor of protein phosphatase 2A 76 (PP2A) in cancer cells [8] . Previous studies have shown that many of the known 77 actions of CIP2A are mediated through inhibition of PP2A [9] , [10] . Overexpression 78 of CIP2A has been associated with the poor prognosis in several human malignancies, 79 and CIP2A has thus been seen as a potential therapeutic target for cancer therapy [8] 80 , [11] , [12] . CIP2A supports the activity of many critical onco-proteins (Akt, MYC, 81 E2F1) and promotes malignancy in most cancer types via PP2A inhibition [8] . 82 Structurally, CIP2A forms a homodimer and this dimerization promotes its interaction 83 with the PP2A regulatory subunits B56a and B56g [13] . Interestingly, inhibition of 84 either CIP2A dimerization or B56a/g expression destabilizes CIP2A in cancer cells ...

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Cyclosporine modulates neutrophil functions via the SIRT6–HIF‐1α–glycolysis axis to alleviate severe ulcerative colitis

Lü

Lin

et al. 2021

Clinical & Translational Med

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Background Cyclosporine A (CsA) is routinely used to treat patients with steroid‐refractory acute severe ulcerative colitis (ASUC). Here, we studied the underlying mechanisms of CsA‐mediated alleviation in ASUC patients. Methods Neutrophil functions including expression of cytokines, apoptosis, and migration were measured by qRT‐PCR, flow cytometry, and Transwell assay. Dynamic changes of glycolysis and tricarboxylic acid (TCA) cycle were measured by a Seahorse extracellular flux analyzer. Gene differences were determined and verified by RNA sequencing, qRT‐PCR, and Western blotting. Small interfering RNA and inhibitors were used to knock down Sirtuin 6 (SIRT6) in HL‐60 cells and block expression of SIRT6, hypoxia‐inducible factor‐1α (HIF‐1α), and pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) in neutrophils. Results We found that HIF‐1α expression and glycolysis significantly increased, while the release of IL‐8, myeloperoxidase (MPO) and reactive oxygen species (ROS), the apoptosis, and ability of migration markedly decreased in neutrophils of ASUC patients who responded to CsA (Response group) compared with those who did not respond to CsA (Nonresponse group). We also observed that CsA‐induced functional alternation of neutrophils was initiated through suppressing SIRT6 expression, which is responsible for expression of the downstream signaling molecules (e.g., HIF‐1α, PFKFB3) and PDK4 ubiquitination, leading to fueling neutrophil glycolysis and TCA cycle. Furthermore, blockage of SIRT6 signaling demonstrated to be the same functional changes as CsA to decrease the migration of neutrophils. Conclusions The data reveal a novel mechanism of CsA in alleviating ASUC by promoting neutrophil HIF‐1α expression and restricting excessive neutrophil activation in a SIRT6−HIF‐1α−glycolysis axis, suggesting SIRT6 as a candidate target for maintaining mucosal homeostasis and treating intestinal inflammation.

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Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

Cited by 48 publications

References 49 publications

LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells

Cyclosporine modulates neutrophil functions via the SIRT6–HIF‐1α–glycolysis axis to alleviate severe ulcerative colitis

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Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

Cited by 48 publications

References 49 publications

LRCH1 suppresses migration of CD4+ T cells and refers to disease activity in ulcerative colitis

LRCH1 suppresses migration of CD4+ T cells and refers to disease activity in ulcerative colitis

Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells

Cyclosporine modulates neutrophil functions via the SIRT6–HIF‐1α–glycolysis axis to alleviate severe ulcerative colitis

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LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis