STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia.
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ABSTRACT:
SUBMITTER: Jiang X
PROVIDER: S-EPMC5260978 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-?, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-?. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-?. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
| S-EPMC3563924 | biostudies-literature
Project description:BackgroundAcute pericarditis as a sign of mediastinal mass is rare and aetiological diagnosis can be challenging without adequate imaging.Case summaryAn 18-year-old woman came to our attention describing acute sharp chest pain radiated to the left arm, exacerbated with supine positioning and attenuated while sitting or leaning forward. The electrocardiogram showed diffuse ST elevation and PR depression, with sinus tachycardia. Cardiac biomarkers and D-dimer were negative; echocardiography showed no abnormalities and the absence of pericardial effusion. Her blood work revealed no sign of inflammation or bacterial infection (PCR and procalcitonin were normal); thyroid-stimulating hormone plasma levels were suppressed, showing decompensated thyrotoxicosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Epstein-Barr virus, human immunodeficiency virus, hepatitis C virus, Enterovirus, Parvovirus B19, and Adenovirus tests were normal. Her past medical history was silent, apart from Grave's disease on treatment with methimazole. Chest computed tomography (CT) was performed and showed the presence of slightly increased density pericardial effusion, with a maximum thickness of 15 mm in the upper mediastinum. Finally, cardiac magnetic resonance (MR) identified a mass of 73 × 51 mm located in the upper mediastinum. The mass was subsequently biopsed with video-assisted thoracoscopic surgery and the histological analysis showed thymic hyperplasia.DiscussionThis case shows the importance of an adequate clinical suspicion of thymic hyperplasia in the context of acute pericarditis symptoms and known Graves' disease. In this case, a negative chest CT finding may not be sufficient to rule out the diagnosis and cardiac MR imaging is necessary.
| S-EPMC8526917 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH), a common disease in elderly males, is accompanied by non-malignant growth of prostate tissues, subsequently causing hypoxia and angiogenesis. Although VEGF-related angiogenesis is one of the therapeutic targets of prostate cancer, there is no previous study targeting angiogenesis for treatment of BPH. Dihydrotestosterone (DHT)- induced expressions of vascular endothelial growth factor (VEGF) in prostate epithelial RWPE-1 cells and human umbilical vascular endothelial cells (HUVECs). Conditioned media (CM) from DHT-treated RWPE-1 cells were transferred to HUVECs. Then, 6SL inhibited proliferation, VEGFR-2 activation, and tube formation of HUVECs transferred with CM from DHT-treated RWPE-1 cells. In the rat BPH model, 6SL reduced prostate weight, size, and thickness of the prostate tissue. Formation of vessels in prostatic tissues were also reduced with 6SL treatment. We found that 6SL has an ameliorative effect on in vitro and in vivo the BPH model via inhibition of VEGFR-2 activation and subsequent angiogenesis. These results suggest that 6SL might be a candidate for development of novel BPH drugs. [BMB Reports 2019; 52(9): 560-565].
| S-EPMC6774418 | biostudies-literature
Project description:Background NCOR1 (nuclear receptor corepressor 1) is an essential coregulator of gene transcription. It has been shown that NCOR1 in macrophages plays important roles in metabolic regulation. However, the function of macrophage NCOR1 in response to myocardial infarction (MI) or vascular wire injury has not been elucidated. Methods and Results Here, using macrophage Ncor1 knockout mouse in combination with a mouse model of MI, we demonstrated that macrophage NCOR1 deficiency significantly reduced infarct size and improved cardiac function after MI. In addition, macrophage NCOR1 deficiency markedly inhibited neointimal hyperplasia and vascular remodeling in a mouse model of arterial wire injury. Inflammation and macrophage proliferation were substantially attenuated in hearts and arteries of macrophage Ncor1 knockout mice after MI and arterial wire injury, respectively. Cultured primary macrophages from macrophage Ncor1 knockout mice manifested lower expression of inflammatory genes upon stimulation by interleukin-1β, interleukin-6, or lipopolysaccharide, together with much less activation of inflammatory signaling cascades including signal transducer and activator of transcription 1 and nuclear factor-κB. Furthermore, macrophage Ncor1 knockout macrophages were much less proliferative in culture, with inhibited cell cycle progression compared with control cells. Conclusions Collectively, our data have demonstrated that NCOR1 is a critical regulator of macrophage inflammation and proliferation and that deficiency of NCOR1 in macrophages attenuates MI and neointimal hyperplasia. Therefore, macrophage NCOR1 may serve as a potential therapeutic target for MI and restenosis.
| S-EPMC7792266 | biostudies-literature
Project description:CD8(+) T cells can be important effector cells in autoimmune inflammation, generally because they can damage target cells by cytotoxicity. This study shows that activated CD8(+) T cells induce thyroid epithelial cell hyperplasia and proliferation and fibrosis in IFN-?(-/-) NOD.H-2h4 SCID mice in the absence of CD4(+) T cells. Because CD8(+) T cells induce proliferation rather than cytotoxicity of target cells, these results describe a novel function for CD8(+) T cells in autoimmune disease. In contrast to the ability of purified CD8(+) T cells to induce thyrocyte proliferation, CD4(+) T cells or CD8 T cell-depleted splenocytes induced only mild thyroid lesions in SCID recipients. T cells in both spleens and thyroids highly produce TNF-?. TNF-? promotes proliferation of thyrocytes in vitro, and anti-TNF-? inhibits development of thyroid epithelial cell hyperplasia and proliferation in SCID recipients of IFN-?(-/-) splenocytes. This suggests that targeting CD8(+) T cells and/or TNF-? may be effective for treating epithelial cell hyperplasia and fibrosis.
| S-EPMC3280124 | biostudies-literature
Project description:Background Thyrotoxicosis is a generally common endocrine condition. Widespread radiologic studies and interventional treatments can increase the prevalence of contrast-induced thyrotoxicosis. Case presentation A younger Thai female was diagnosed acute appendicitis that underwent computed tomography of abdomen with contrast injection. After the operation, she had fever and tachycardia without source of infection, but her thyroid function test showed hyperthyroidism, so she was diagnosed graves’ disease and received the treatment without thyroid storm. Discussion Graves' disease is the most prevalent cause of hyperthyroidism in women but there are many causes of hyperthyroidism especially contrast-induced hyperthyroidism in this care, so the necessary of diagnostic tools especially contrast computed tomography should be carefully used in some patients. Conclusion Critical radiologic studies and interventional procedures can increase the prevalence of contrast-induced thyrotoxicosis, particularly in high-risk patients. Utilizing a multidisciplinary team, clinicians must promptly address thyrotoxicosis and avert the thyroid storm. Highlights • Thyrotoxicosis is a relatively common endocrine disorder.• Thyrotoxicosis refers to the clinical symptoms of excess circulating thyroid hormones such as thyroiditis, and iodine-induced or drug-induced thyroid dysfunction.• Diagnosis of thyrotoxicosis is upon clinical examination, laboratory tests, and further investigation to assist with diagnosing the specific cause and to arrange necessary treatment.• The important issue among patients with thyrotoxicosis needing an operation is perioperative management and multidisciplinary care to prevent the thyroid storm that increases morbidity and mortality.
| S-EPMC9577527 | biostudies-literature
Project description:Connexin (Cx)30, which forms gap junction interconnecting astrocytes, regulates cell adhesion and migration and modulates glutamate transport. The expression levels of Cx30 are known to be upregulated on the activated astroglia at CNS inflammation lesion, including mutant-SOD1 transgenic ALS model mice spinal cord lesion. We aimed to clarify the role of Cx30 in mSOD1-transgenic mice. Cx30 was highly expressed in the pre-clinical stage of mSOD1-Tg mice. Cx30-knockout mSOD1 mice showed a delayed onset and tended to extend the survival period (log-rank, p = 0.09). At the progressive and end stages, anterior horn cells were more preserved in Cx30-knockout mSOD1 mice. Additionally, dorsal horn cells were kept more in Cx30-knockout mSOD1 mice at all stages. In the lesion of Cx30-knockout mSOD1 mice, GFAP and C3 positive inflammatory astroglia were decreased. Further, in Cx30-knockout mSOD1 mice, the amount of NOS2 protein at the end stage and the amount of Cx43 protein at the pre-clinical stage were smaller than in mSOD1 mice. These findings indicated reduced expression of astroglial Cx30 in the early stage of ALS model mice protects neurons by the attenuation of glial inflammation.
2022-09-24 | GSE213844 | GEO
Project description:The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.
| S-EPMC9109499 | biostudies-literature
Project description:Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can't achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
| S-EPMC6941101 | biostudies-literature
Project description:BackgroundAutoimmune thyroid disease (AITD), one of the most prevalent organ-specific autoimmune diseases, mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). This study was aimed at researching the association between AITD and single nucleotide polymorphisms (SNPs) of the HLA-DRA gene.MethodsUsing Hi-SNP high-throughput sequencing technology, we detected the distribution of three SNPs (rs3177928, rs7197, and rs3129878) of HLA-DRA genotypes in 1033 AITD patients (634 GD and 399 HT ones) and 791 healthy volunteers in Chinese Han Population. Chi-square test, multivariate logistic regression, and haplotype analysis were performed by SPSS and Haploview software to analyze the relationship between HLA-DRA gene polymorphisms and AITD.ResultsThe results show that allele frequency and genotype distribution of rs3177928 and rs7197 were correlated with AITD and GD compared with the healthy control group, but not with HT. Rs3177928 and rs7197 were correlated with AITD and HT in the allele model, dominant model, and overdominant model before and after gender and age adjustment, but not with HT. In addition, we found that two loci (rs3177928 and rs7197) constituted a linkage disequilibrium (LD) region, and haplotype AA was associated with AITD and GD. However, we found no association between rs3129878 and AITD.ConclusionOur study is the first to find that rs3177928 and rs7197 of HLA-DRA are significantly correlated with AITD and GD in the Chinese Han population. This will help further reveal the pathogenesis of AITD and provide new candidate genes for the prediction or treatment of AITD.
| S-EPMC9484895 | biostudies-literature