Mutant glucocorticoid receptor binding elements on the interleukin-6 promoter regulate dexamethasone effects

Abstract Background Glucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines, such as interleukin (IL)-6. Results Five putative GR binding sites and other transcriptional factor binding sites were identified on theIL-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, nuclear factor-kappa B (NF-κB), activator protein (AP)-1, and specificity protein (Sp)1–2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The second GR binding site (GR2) was noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation. Conclusions We concluded that selective GR2 modulator might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process.

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Mutant Glucocorticoid Receptor Binding Elements on the Interleukin-6 Promoter Regulate Dexamethasone Effects

10.21203/rs.3.rs-66194/v1 ◽

2020 ◽

Author(s):

Wen-Teng Chang ◽

Ming-Yuan Hong ◽

Chien-Liang Chen ◽

Chi-Yuan Hwang ◽

Cheng-Chieh Tsai ◽

...

Keyword(s):

Binding Sites ◽

Inflammatory Process ◽

Inflammatory Diseases ◽

Inducible Promoter ◽

Transcriptional Factor ◽

Factor Binding ◽

Inflammatory Processes ◽

Nuclear Receptor Family ◽

Receptor Family ◽

Pro Inflammatory Cytokines

Abstract BackgroundGlucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines. ResultsFive putative GR binding sites and other transcriptional factor binding sites were identified on the interleukin (IL)-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, NF-κB, AP-1, and Sp1-2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The first and third GR binding sites (GR2 and GR3) were noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation. ConclusionsWe concluded that selective GR2 and GR3 modulators might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process.

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Sequence Characterization of S100A8 Gene Reveals Structural Differences of Protein and Transcriptional Factor Binding Sites in Water Buffalo and Yak

Animal Biotechnology ◽

10.1080/10495398.2011.581558 ◽

2011 ◽

Vol 22 (3) ◽

pp. 124-132

Author(s):

P. Kathiravan ◽

S. Goyal ◽

R. S. Kataria ◽

B. P. Mishra ◽

S. Jayakumar ◽

...

Keyword(s):

Binding Sites ◽

Water Buffalo ◽

Transcriptional Factor ◽

Sequence Characterization ◽

Factor Binding ◽

Structural Differences

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The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19123851 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3851 ◽

Cited By ~ 38

Author(s):

Drew Neavin ◽

Duan Liu ◽

Balmiki Ray ◽

Richard Weinshilboum

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Nuclear Receptor ◽

Binding Sites ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

Aryl Hydrocarbon ◽

Inflammatory Processes ◽

Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

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