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Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
The intestinal lamina propria contains many CD4 T lymphocytes that probably have a fundamental role in mucosal tolerance and host defense in the healthy intestine. Regulatory T cells in particular have been identified as a T-cell subset with anti-inflammatory properties in the gut. These cells express CD25 and the transcription factor Foxp3 and are known to counteract the function of mucosal effector T cells. The number of T cells with a normal regulatory function is increased in IBD. This is consistent with there being a marked expansion of effector T cells in IBD that cannot be adequately controlled by these regulatory T cells (see Figure 34.7). Effector T lymphocytes in IBD are activated in IBD via antigen-presenting cells and luminal antigens. They show elevated cell proliferation and the activation of T-cell receptor-inducible transcription factors such as NFATc2. Furthermore, specific signature cytokines are produced by these cells in active IBD that permit their classification into helper-T-cell subsets. For instance, lamina propria T cells in Crohn's disease produce larger amounts of TH1 cytokines such as IFN-γ on stimulation and express the TH1 transcription factor T-bet. In ulcerative colitis, however, T cells produce increased amounts of some TH2 cytokines such as IL-5 and IL-13. In contrast, IL-4 production by these cells is lower than in controls, suggesting the presence of an atypical TH2 cytokine profile. However, neutralization of IL-13 (tralokinumab) in patients with ulcerative colitis did not improve disease severity. In addition, a novel IL-9 producing T-cell subpopulation (TH9) has been identified that is significantly increased in the mucosa of ulcerative colitis patients. In addition to prototypical TH1, TH2, or TH9 cytokines, large amounts of disease-perpetuating cytokines such as TNF-α and IL-6 are produced by lamina propria T cells in IBD as well as in cells associated with the innate immune system.
Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo
Published in Journal of Liposome Research, 2022
Gang Wang, Yu Yang, Du Yi, Lu Yuan, Pei-Hao Yin, Xu Ke, Wang Jun-Jie, Min-Fang Tao
Studies have found that the up-regulated expression of TLR genes was accompanied with enhanced tumor invasion and metastasis (Maierbrugger et al.2020). Under the pH-BA-LP treatment, the expression of TLR-4 protein significantly decreased, and pH-BA-LP or BA may participate in inhibiting tumor invasion and metastasis via down-regulating the expression of TLR-4 and TLR-9 protein. NFAT is related to a variety of signal transduction pathways such as immune response regulation, T cell growth and differentiation, and cell apoptosis (Maierbrugger et al.2020). Our previous study has suggested that BA had a significant effect on the expression of NFAT1 protein in HCT116 cells. In this study, we also found that the pH-BA-LP could down-regulate the expression of NFAT1 and NFAT4 proteins.
NFATc3 inhibits hepatocarcinogenesis and HBV replication via positively regulating RIG-I-mediated interferon transcription
Published in OncoImmunology, 2021
Xiaobin Zao, Jin Cheng, Congle Shen, Guiwen Guan, Xiaoyu Feng, Jun Zou, Jing Zhang, Tianxu Liu, Huiling Zheng, Ting Zhang, Jie Wang, Jia Liu, Deyao Li, Fengmin Lu, Fuping You, Xiangmei Chen
Based on the data from The Cancer Genome Atlas (TCGA), we investigated the expression of NFATc3 in HCC. The results showed that NFATc3 expression was downregulated in HCC tissues (Figure 1a) and the lower NFATc3 expression was significantly correlated with the poor 5-year overall survival (OS) in patients with HCC (n = 343, P= .048) (Figure 1b). Consistently, we confirmed that the mRNA level of NFATc3 in tumor tissues was significantly lower than that in paired para-tumor tissues, and both were significantly lower than that in normal liver tissues in our HBV-related HCC cohort (Figure 1c). The downregulation of NFATc3 was further confirmed at the protein level in five pairs of HBV-related HCC tissues (Figure 1d). In line with the survival data from TCGA, patients with lower NFATc3 mRNA expression had significantly lower 5-years OS rate (P= .021) than those with higher NFATc3 expression (Figure 1e) in our HBV-related HCC cohort. Moreover, we investigated the correlations between the expression status of NFATc3 and clinical parameters including tumor size, tumor number, TNM stage and BCLC stage, but no significant correlation was found (Table S2). We also analyzed the expression and clinical significance of NFATc1, NFATc2 and NFATc4 in TCGA database. However, no survival prognosis associations between these genes expression and HCC patients were observed (Supplementary Figure 1a). These results indicated that NFATc3 expression was downregulated in HCC and might be related to the development and progression of HCC.
Cordycepin exhibits a suppressive effect on T cells through inhibiting TCR signaling cascade in CFA-induced inflammation mice model
Published in Immunopharmacology and Immunotoxicology, 2020
Xiaoli Wang, Deshuang Xi, Jian Mo, Ke Wang, Yu Luo, Erbin Xia, Rong Huang, Shunrong Luo, Jiao Wei, Zhenghua Ren, Hui Pang, Rirong Yang
NF-κB, NFAT, and MAPK are the most relevant transcription factors in downstream of TCR signaling [9–11]. In previous study, we have illustrated a detailed molecular mechanism of cordycepin in suppression of NF-κB signaling pathway [32]. More investigations about the inhibitory effect of cordycepin on NF-κB expression have been performed [33–35]. Thus, we mainly examine the effect of cordycepin on Erk1/2 and NFAT1. In MAPK signaling pathway, cordycepin suppresses LPS-induced Erk1/2 phosphorylation in BV2 microglial cells [34], and a similar observation that cordycepin suppresses Erk1/2 phosphorylation in T cells is obtained in this study. Furthermore, it is detected that a weak inhibitory effect of cordycepin on Erk phosphorylation in mouse T cells [28]. These data indicate that cordycepin is able to suppress TCR signaling to regulate MAPK pathway in T cells. NFAT1 is involved in T-cell activation and proliferation [9–11]. In TCR signaling transduction, NFAT1 is translocated from the cytoplasm to the nucleus. In our experiment, results show that cordycepin inhibits NFAT1 nuclear translocation, indicating that cordycepin inhibits the immune competence of T cells partly by reducing NFAT1 nuclear transfer.