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Interleukin-1
Published in Jason Kelley, Cytokines of the Lung, 2022
Timothy R. Aksamit, Gary W. Hunninghake
The specific mechanisms for regulation of IL-1 transcription remain unclear (Clark et al., 1986). However, examination of the IL-1 genes for known regulatory elements has revealed some regions that may be important for transcriptional control. Both IL-1α and IL-1β have Sp1-binding sites and glucocorticoid-responsive elements in their 5′ flanking regions and introns. The IL-1β gene also contains TATA and CAAT box sequences, several viral enhancerlike sequences, and a cAMP response element (CRE) (Clark et al., 1986; Akira et al., 1990a; Ohmori et al., 1990). Interleukin-1α appears to have an AP-1-binding site and a sequence similar to the adenovirus-2 major late promoter transcription factor-binding sequence in proximity to a TATA-like sequence. No CAAT or CRE sequences are found in the IL-1α gene. A sequence that binds a DNA-binding protein, hNFIL-1βA, is in close proximity to the IL-1β TATA box (Fenton, 1990). This sequence appears to be important for basal regulation of the IL-1β gene and may also be important for regulation of expression of the gene following exposure to endotoxin.
Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Expression of the c-fos gene is frequently associated, in a manner similar to that of c-myc, with the processes of cell proliferation and/or differentiation.359 Cellular Fos proteins are localized in the nucleus and are involved in the control of genomic functions through the formation of transcriptional complexes with Jun proteins. The Jun/Fos complexes recognize the AP-1 binding site at the DNA level.
Interleukin 6: Role in the Pathogenesis of Cancer
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Interleukin 6 can be produced by several types of cells, including T lymphocytes, monocyte/macrophages, fibroblasts, epithelial cells, endometrial cells, and various tumor cells [4–7]. Gene expression of IL-6 can be induced by a wide range of stimuli, including other cytokines (IL-1, tumor necrosis factor [TNF], and platelet-derived growth factor [PDGF]); microbial products, including lipopolysaccha-ride (LPSs); and various viruses, including the human immunodeficiency virus (HIV), specifically, the HIV gp41 env protein, a virally encoded envelope protein involved in virus-cellular membrane fusion [4–7,21]. The transcriptional regulation of IL-6 gene expression has been elucidated in recent work [4–7,22]. The IL-6 promoter region contains several transcriptional control elements with potential activity: a glucocorticoid-responsive element (GRE), an AP-1 binding site, a c-fos serum-responsive element (SRE), a cyclic adenosine monophosphate-(cAMP)-responsive element, an NF-κB-binding site, a multiresponse element (MRE), and a 14-bp palindromic sequence recognized by NF-IL6, a nuclear transcription factor [22]. The NF-IL6 protein has some homology with the fos and myc oncogene products, and interacts with the NF-IL6-binding motif (AGATTGCACAATCT) within the IL-6 gene regulatory region, inducing IL-6 gene expression. Normally, NF-IL6 is not expressed, but its expression is induced by exposure of IL-6-producing cells to various inducers of IL-6 gene expression. Cytokines, including TNF and IL-1, rapidly and transiently activate the IL-6 promoter. The 23-bp MRE regulatory region, which is located within the c-fos SRE; the NF-IL6-binding site; and the NF-κB-binding site; all may be involved in the induction of IL-6 gene expression by IL-1 or TNF [4–7,22]. Therefore, at least three regions appear to be involved in the regulation of IL-6 gene expression.
Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation
Published in Gut Microbes, 2020
Lingyu Wang, Zizhen Gong, Xiuyuan Zhang, Fangxinxing Zhu, Yuchen Liu, Chaozhi Jin, Xixi Du, Congfeng Xu, Yingwei Chen, Wei Cai, Chunyan Tian, Jin Wu
To figure out the connection between bile acid receptor M2-mAchR and TLR2 expression under DCA stimulation, murine macrophages were treated with DCA in the presence or absence of M2-mAchR selective inhibitor, mRNA and protein levels of TLR2 were determined by real-time PCR and western blot respectively. Indeed, M2-mAchR blockage almost reduced TLR2 expression to the baseline level (Figure 6(a,b)). To better understand the regulatory mechanism of TLR2 expression directed by DCA, luciferase activity assay was conducted by using a 2000-bp TLR2 promoter reporter plasmid. As expected, luciferase activity markedly increased upon DCA stimulation and was efficiently eliminated by M2-mAchR inhibitor (Figure 6(c)). The subsequent deletion analysis exhibited that deletion of −2000 to −1500 bp region significantly reduced the TLR2 promoter activity in response to DCA, suggesting that the critical DCA-related responsive element seems to be located in this distal portion of TLR2 promoter (Figure 6(d)). Notably, an important AP-1 binding site within above region was predicted by bioinformatics analysis, together with the observation showing that AP-1 inhibitor could greatly diminish the TLR2 promoter activity induced by DCA (Figure 6(e)), these data indicate that DCA regulates TLR2 transcription mainly by targeting AP-1. To confirm this result, chromatin immunoprecipitation (ChIP) assay was performed using a c-Jun-specific antibody. Data showed that c-Jun antibody pulled down much more AP-1 binding region sequences on TLR2 promoter in DCA-treated macrophages than untreated control, and consist with previous findings, M2-mAchR inhibitor substantially reversed this effect (Figure 6(f) and Supplementary Figure 5). In addition, both M2-mAchR inhibitor and AP-1 inhibitor used here have no obvious effect on macrophage viability (Supplementary Figure 3b).