The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription

Simon, Priscilla S.; Sharman, Sarah K.; Lu, Chunwan; Yang, Dafeng; Paschall, Amy V.; Tulachan, Sidhartha; Liu, Kebin

doi:10.1186/s12885-015-1808-6

Cited by 52 publications

(52 citation statements)

References 60 publications

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“…The target genes of Irf8 include Fas, Bax, FLIP, STAT1 and iNOS, suggesting an essential role of Irf8 in apoptosis. 58-62 Consistently, knockdown of Irf8 attenuated cisplatin-induced apoptosis in RPTC cells (Figure 7). Thus, hypomethylation of Irf8 during cisplatin-induced AKI may lead to the up-regulation of this pro-apoptotic transcription factor for tubular cell injury and death.…”

Section: Discussionsupporting

confidence: 54%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic and coding DNA sequences, some were located in the promoter or promoter regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of DNA methylation inhibitor 5-Aza-2′-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

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Section: Discussionsupporting

confidence: 54%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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“…It was reported that several key genes in the inflammatory process such as NF- κ B provide a mechanistic link between inflammation and cancer [45–48]. Activation of TLRs and TNFR leads to NF- κ B activation and induced the expression of many proinflammatory molecules including NO synthase 2 (iNOS) [49, 50]. A growing number of studies have reported the key role of TLR4/NF- κ B/TNF- α signaling to promote tumor growth in experimental models of colitis associated cancer [44, 51–53], whereas data from human CAC are rare.…”

Section: Discussionmentioning

confidence: 99%

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer

Rafa

Benkhelifa

Ait-Younes

et al. 2017

Mediators of Inflammation

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Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.

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“…In myeloid cells, particularly in macrophages, TNFα and LPS/TLR ligands-activated NF-κB is a major regulator of iNOS expression (27, 28, 42, 43). NF-κB, once activated by LPS or TNFα, can activate iNOS expression (28, 44). The p65 and p50 homodimers of the canonical NF-κB directly binds to the nos2 promoter region to activate nos2 transcription in myeloid cells (28).…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB, once activated by LPS or TNFα, can activate iNOS expression (28, 44). The p65 and p50 homodimers of the canonical NF-κB directly binds to the nos2 promoter region to activate nos2 transcription in myeloid cells (28). In addition to NF-κB, inflammatory cytokines such as IFN-γ have also been shown to regulate iNOS expression (27, 45).…”

Section: Discussionmentioning

confidence: 99%

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

et al. 2017

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Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T cell receptor and STAT1, thus inhibiting T cell activation and the anti-tumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSC, iNOS expression was significantly elevated in tumor-induced MDSC, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathological conditions. Furthermore, tumor-induced MDSC exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSC showed increased SETD1B expression as compared to their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSC, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSC. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSC, when they are generated under pathological conditions.

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The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription

Cited by 52 publications

References 60 publications

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

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