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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
As mentioned previously, macrophages exert direct actions on fibroblasts affecting cardiac fibrosis and repair. In the murine MI model, exosomes secreted by macrophages contain miR-155 (71). Exosome uptake by fibroblasts restrains their proliferation by regulating the expression of son of sevenless-1 (Sos1), while it induces the expression of pro-inflammatory cytokines, such as IL-1β, IL-6, tumor necrosis factor-α (TNFα), and MCP-1/CCL2, through the inhibition of signaling by the suppressor of cytokine signaling 1 (Socs1)/signal transducer and activator of transcription 3 (STAT3) pathway. These events contribute to detrimental remodeling, promoting cardiac rupture in the post-MI heart, an effect abolished following miR-155 deficiency (71) (Figure 5.2). Another microRNA, miR-21, the most highly expressed microRNA in cardiac macrophages in healthy hearts, becomes further upregulated in HF. In fact, the cardiac dysfunction caused by pressure overload injury (TAC model) was partially rescued upon miR-21 knockdown in murine macrophages (72). Importantly, not only did miR-21 favor the M1 type of macrophage activation but its secretion was enhanced upon this pro-inflammatory activation and mediated the differentiation of cardiac fibroblasts to myofibroblasts (Figure 5.1), an event inhibited by locked nucleic acid (LNA)-anti-miR-21 inhibition (72).
Mechanisms of Hepatitis C Virus Clearance by Interferon and Ribavirin Combination
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Srikanta Dash, Partha K. Chandra, Kurt Ramazan, Robert F. Garry, Luis A. Balart
Over the past several years, many studies have been performed to understand how the mechanisms of IFN-α antiviral action against HCV are impaired by cellular and viral proteins (Blindenbacher et al. 2003; Bode et al. 2003; Duong et al. 2004, 2006, 2010; Lin et al. 2006; Randal et al. 2006; Christen et al. 2007; Kim et al. 2009; Sarasin-Filipowicz et al. 2009; Bellecave et al. 2010). These reports indicate that IFN-α signaling is controlled by a number of negative regulators such as suppressor of cytokine signaling (SOCS), ubiquitin-specific peptidase 18 (USP18), protein inhibitor of STAT1 (PIAS), and protein phosphatases. The SOCS family members, SOCS1 and SOCS3, prevent Stat phosphorylation by inhibiting the IFN-α receptor-associated Jak kinases (Kim et al. 2009). PIAS1 inhibits binding of STAT1 dimers to the response elements in the promoter region of the IFN-target genes. The upregulation of protein phosphatase 2A (PP2A) in HCV-infected cells inhibits IFN-α signaling. USP18 is a classical ISG that provides a strong negative feedback loop at the level of the receptor kinase complex. The mechanisms by which many patients develop resistance to RBV are not well understood. One group reported that reduced RBV uptake by HCV-infected cells contributed to an impaired antiviral response (Ibarra and Pfeiffer 2009; Ibarra et al. 2011). These investigators demonstrated that RBV uptake was reduced in the infected cells. No additional systematic study has been performed to understand how the IFN-α and RBV synergistic antiviral mechanism is impaired in HCV infection.
Primary mediastinal (thymic) large B-cell lymphoma
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Kerry J Savage, Philippe Gaulard
In addition to evidence of activation of NF-κB, it has been further shown that PMBCL activates the JAK–STAT signaling pathways,23,34 with phosphorylated STAT6 detected in the nuclei of PMBCL, being also found in cHL23,36,42 (Figure 18.1f). As outlined above, activation of the JAK–STAT signaling pathway seems to be frequently related to mutations in SOCS1.34–36
Epigenetic regulation of radioresistance: insights from preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2022
Katherine Shishido, Alexis Reinders, Swapna Asuthkar
The suppressors of cytokine signaling (SOCS) are a family of signal transduction regulators that mediate oncogenic signaling and radiosensitivity. SOCS1 appears to act as a tumor suppressor [77,78]. However, studies in pancreatic ductal and hepatocellular carcinoma have indicated that DNMT1-mediated methylation of the SOCS1 promoter is responsible for its repression [79,80]. Moreover, DNMT1 is known to recruit HDACs to induce transcriptional repression [81] with studies showing that SOSC1 is also regulated by histone acetylation [82]. For instance, Kim et al. demonstrated that CpG sites on the SOCS1 promoter are heavily methylated; however, treatment with either 5-Aza or the HDAC inhibitor, trichostatin A, induced its expression [83]. Notably, exogenous expression of SOCS1 significantly attenuated radiosensitivity in vitro, indicating that DNMT1-HDAC promotes radiosensitivity via SOCS1 suppression (Table 4). Similarly, Zhou et al. showed that CpG islands on the SOCS promoter are heavily methylated in glioblastoma cells [84]. Interestingly, ectopic expression of SOCS1 enhanced radiosensitivity and attenuated ERK1/2 activation, suggesting that methylation-induced silencing of SOCS1 promotes RR through ERK1/2 activation.
A blockade of microRNA-155 signal pathway has a beneficial effect on neural injury after intracerebral haemorrhage via reduction in neuroinflammation and oxidative stress
Published in Archives of Physiology and Biochemistry, 2022
Wenwen Zhang, Luping Wang, Ruimin Wang, Zongsheng Duan, Hushan Wang
Accumulated evidence has demonstrated critical roles played by various miRNAs in modifying pathophysiological processes with animal models and clinical ischaemic disorders (Karthikeyan et al., 2016, Khoshnam et al., 2017, Roitbak, 2018). Specifically, it was reported that anti-inflammatory protein suppressor of cytokine signalling 1 (SOCS1) is one of the target genes of miR-155 (Cardoso et al., 2012). SOCS1 is a critical regulator of inflammation and negatively regulates the feedback of inflammation (Yasukawa et al., 2000). Deficiency of SOCS1 results in amplified responsiveness to inflammation in cells and/or in animals (Hanada et al., 2003, Chinen et al., 2006). MiR-155 is also involved in regulating stroke development by promoting expression of TNF-α and IL-1β and by decreasing SOCS1 (Eisenhardt et al., 2015, Wen et al., 2015). Thus, more investigations are needed to define the networks of miR-155 in involvement of development of neurological deficits due to ICH.
Development of molecular intervention strategies for B-cell lymphoma
Published in Expert Review of Hematology, 2021
SOCS1 (located on 16p13.3) is a tumor suppressor gene coding for a 211-amino acid protein made of a central SH2 (Src homology) domain that distinguishes target proteins that are ubiquitinated and target them to the proteasome by the E3 ligase complex bound to the SOCS box and a C-terminal domain called the SOCS box. Abnormal JAK/STAT signaling pathway has been observed in hematological malignancies [71,72]. Besides, SOCS1 also binds to the tumor suppressor p53 but does not stimulate its degradation [73]. A recent report shows that the ability of the p53-SOCS1 axis to regulate cell aging depends on the structural motif of tyrosine (Y) 80 in the SH2 domain of SOCS1 [73]. The substitution of Y80 with phosphite like residues can inhibit the interaction of p53-SOCS1 and stimulate p53 transcription activity, growth arrest, and cell aging. Src family kinase inhibitors can phosphorylate SOCS1, lead to its homodimerization, inhibit its interaction with p53, and enhance SOCS1 induced aging, which suggests that f-Src family kinase inhibitors (dasatinib) may be an effective method for individualized treatment for lymphoma patients [73,74].