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Overview of JAK-STAT Pathways in Spondyloarthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Smriti K. Raychaudhuri, Sanchita Raychaudhuri, Debasis Bagchi, Anand Swaroop, Siba P. Raychaudhuri
JAK1 and JAK2 have been demonstrated to play an important role in Th1 and Th17 cell differentiation, while STAT1 is critical to T-lymphocyte differentiation. STAT1 is activated by type I IFNs and IFN-γ and plays an important role in immune responses. IRF1 is the first member identified in the interferon-regulatory factor (IRF) family and is involved in innate and adaptive immune responses. Impaired or absent Th1-type immune responses favor Th2 differentiation in IRF1-deficient mice. NOS2-derived nitric oxide (NO), a key factor in immunoregulation, can inhibit Th1 as well as Th2 cytokine production and regulate the development of FoxP3+ Treg cells. JAK-STAT signaling pathway genes, including JAK1, JAK2, STAT1, IRF1, and NOS2, are strongly linked to T cells and may be involved in the pathophysiology of acute anterior uveitis (AAU), AS, psoriasis, and psoriatic arthritis (PsA).
Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Other infrequently observed alterations found in gastric cancer include the amplification of AKT-1, CYCLIN E1 (CCNE1), YES1, and ERBB1 (Nomura et al., 1986; Ochiai et al., 1997; Seki et al., 1985; Staal, 1987). Mutation analysis of p300 has found at least one gastric cancer case with a somatic mutation in the functionally important Cys/His region coupled with deletion of the second allele (Muraoka et al., 1996). Of note, p300 may be the target for deletions of chromosome 22q seen in gastric cancer. Interferon regulatory factor-1 (IRF1) also appears to be mutated in a small percentage of gastric cancers. Nozawa et al. identified a missense mutation in IRF1 in 1/9 gastric cancers. This mutation was accompanied by allelic loss of the second allele and decreased transcriptional activity from the mutant IRF1 (Nozawa et al., 1998). The role these alterations play in sporadic gastric cancer formation remains to be determined.
Molecular Regulation of NO Synthase in the Heart
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Jean-Luc Balligand, Thomas W. Smith
Unlike the consitutive isoforms, NOS2 is mainly regulated at the transcriptional level (Nathan and Xie, 1994). The large variety of agents known to induce NOS2 expression in many cell types is reflected by the complexity of the regulatory elements in the NOS2 promoter. The 5′-flanking region of the NOS2 gene has been partly characterized in both mouse and human species (Lowenstein et al., 1993; Xie et al., 1993; Chartrain et al., 1994; Nunokawa et al., 1994). Both show some structural similarities, with a TATA box 30 base pairs upstream of the initiation transcription site and the presence of several consensus sequences for the binding of transcription factors mediating the cytokine responsiveness, e.g. NF-κ B-binding motifs, INFg response elements, and nuclear factor IL6-binding sites among others. Site-directed mutagenesis in the interferon regulatory factor binding site of the murine promoter abolished the enhanced transcription of NOS2 by INFγ (Martin et al., 1994). In addition, macrophages from homozygous mice deficient for the IRF-1 gene exhibited little or no NOS2 expression or NO production in response to cytokine stimulation, indicating a critical role for IRF-1 in the expression of NOS2 at least in murine macrophages (Kamijo et al., 1994). Whether this cis-regulatory element plays a critical role for the expression of NOS2 in the context of myocytes or endothelial cells from cardiac muscle is unknown. In adult rat heart myocytes treated with INFγ, the abundance of the IRF-1 transcript is decreased by pretreatment with dexamethasone, which also decreases the abundance of NOS2 transcripts (Balligand et al., unpublished results).
Inflammatory response of gut, spleen, and liver in mice induced by orally administered Porphyromonas gingivalis
Published in Journal of Oral Microbiology, 2022
Yingman Liu, Wenkai Huang, Ke Dai, Ni Liu, Jiaqi Wang, Xiaoying Lu, Jiaojiao Ma, Manman Zhang, Mengqi Xu, Xu Long, Jie Liu, Yurong Kou
Inflammatory infiltration in the gut is also an important pathologic change induced by oral administration of P. gingivalis. The mRNA levels of TNF-α, IFN-γ, and IRF-1 were elevated in the gut of SC-P. g mice. TNF-α and IFN-γ are canonical Th1 cytokines. TNF-α, as a pleiotropic cytokine, has been shown to correlate with numerous intestinal diseases such as active celiac disease and IBD [45,46]. Some studies have also demonstrated the overexpression of intestinal TNF-α in patients with Crohn’s disease [47–49], and anti-TNF-α antibody treatment has been used to treat patients with IBD [50,51]. In mucosal tissues of murine colitis models and IBD patients, the level of IFN-γ is highly upregulated. The pathophysiological role of IFN-γ in mucosal tissues of IBD has been ascribed to its immunomodulatory or epithelial effects [52,53]. IRF-1, the first member of the IFN regulatory factor family, exerts effects in various physiological and pathological contexts including inflammatory injury, viral infection, development of the immune system, and autoimmunity [54]. We demonstrated the induction of IRF-1 mRNA expression in the gut of SC-P. g mice, consistent with IFN-γ-initiated signaling events. Thus, orally administered P. gingivalis markedly affected the intestinal physiological environment of mice in the current study.
IRF1 Inhibits Autophagy-Mediated Proliferation of Colorectal Cancer via Targeting ATG13
Published in Cancer Investigation, 2022
Li Yuan, Xiao Zhang, Kai Cheng, Liping Li, Zhongming Guo, Liang Zeng
As a transcription factor, IRF1 binds to many gene promoter areas and regulates their expression. We found that IRF1 could bind to the ATG13 promoter by bioinformatics analysis. To confirm their direct interaction, we conducted the dual-luciferase reporter assay. Results showed that IRF1 significantly reduced the luciferase activity by nearly four-folds in 293 T cells and three-folds in SW480 cells. We also disrupted the putative IRF1 paring sites in promoter by site-directed mutagenesis. The mutated reporters restored IRF1-reduced luciferase activity (Figure 4(A)). The RT-PCR analysis showed that IRF1 inhibited the ATG13 express (Figure 4(B)). Sixty-one pairs of CRC tissues and adjacent normal tissues were immunostained for IRF1 and ATG13 (Figure 4(C)), As shown in Table S1, the IRF1 expression level was significantly higher in the normal tissues than in CRC tissues (p < 0.001) and inversely associated with tumor size (p = 0.001), and there was a negative correlation between IRF1 and ATG13 expression levels (Figure 4(D), p < 0.001).
Nestin and CD34 expression in colorectal cancer predicts improved overall survival
Published in Acta Oncologica, 2021
Athanasios Tampakis, Benjamin Weixler, Silvan Rast, Ekaterini-Christina Tampaki, Eleonora Cremonesi, Venkatesh Kancherla, Nadia Tosti, Christoph Kettelhack, Charlotte K. Y. Ng, Tarik Delko, Savas D. Soysal, Urs von Holzen, Evangelos Felekouras, Nikolaos Nikiteas, Martin Bolli, Luigi Tornillo, Luigi Terracciano, Serenella Eppenberger-Castori, Giulio C. Spagnoli, Salvatore Piscuoglio, Markus von Flüe, Silvio Däster, Raoul A. Droeser
In the present study, nestin and CD34 presented a moderate to strong correlation for CD8, FOXP3, CD4, GATA3, CCL2, CXCL12 and IRF1. In CRC, several studies have shown a significant correlation between T-cell infiltration and improved survival [45]. Interestingly, a recent meta-analysis of studies on solid tumors investigating the clinical significance of tumor-infiltrating lymphocytes (TIL) elucidated that the presence of CD3, CD8, and a high CD8/FoxP3 ratio significantly improved survival [46]. CD4+ T cells' role in tumors has been controversial as they can convert from anti-tumor to pro-tumor cells [47–48]. However, recent data suggest that they can exert anticancer actions by enhancing CD8+ T cells' activity or less often by directly recognizing antigens of the cancer cells’surface with subsequent secretion of type 1 cytokines [49] or direct cancer cell destruction [50]. Besides, increasing evidence underlines the crucial role of GATA3 for the development, differentiation, and function of CD4+ T cell and CD8+ T cells [51]. CCL2 and CXCL12 are highly effective chemotactic factors, recruiting monocytes and lymphocytes, respectively [52–53]. Finally, IRF-1 is a nuclear transcription factor with a critical role in inflammation, immunity, cell proliferation, and apoptosis. It is produced in response to IFN-γ (interferon-γ) [54] and has been demonstrated to help suppressing CRC cell growth and metastasis by providing IRF1/miR-29b feedback loop [55].