Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation and vascular calcification are independent risk factors of cardiovascular events. Vascular smooth muscle cells (VSMCs) exhibit osteoblast-like characteristics in response to various stimuli such as oxidized cholesterol and inflammation. However the precise mechanism of transcriptional regulation of VSMCs by inflammatory stimuli remains unclear. We investigated the process and mechanisms of inflammatory cytokine-induced transformation of human VSMCs (hVSMCs) into osteoblast-like cells, with a special focus on epigenetic changes. Our results demonstrated: (1) interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) induced transformation of hVSMCs into an osteoblast phenotype, with subsequent vascular calcification, based on the results of Alizarin Red S staining and O-Cresolphthalein complexone method; (2) IL-6/sIL-6R accelerated the expression of runt-related transcription factor 2 (RUNX2) based on the results of quantitative real-time polymerase chain reaction; (3) Knockdown of signal transducer and activator of transcription (STAT) 3 reduced IL-6/sIL-6R-induced RUNX2 mRNA expression and osteoblast transdifferentiation of hVSMCs; (4) Chromatin immunoprecipitation (ChIP) coupled with PCR (ChIP-PCR) identified a STAT-binding site in RUNX2 promoter region containing trimethylated histone 3 lysine 9 (H3K9me3), a transcriptional repressor, and H3K4me3, a transcriptional enhancer. Stimulation with IL-6/sIL-6R suppressed H3K9me3 but not H3K4me3 through the recruitment of jumonji domain-containing protein (JMJD) 2B, a histone lysine demethylase, at the STAT-binding site in RUNX2 promoter region; (5) IL-6/sIL-6R-induced RUNX2 gene expression was inhibited in hVSMCs pretreated with JIB04, JMJD2 inhibitor, and the inhibitory effect was JIB04 dose-dependent. Our results indicate that the IL-6/STAT3/JMJD2B pathway regulates hVSMCs differentiation into osteoblast-like cells, which suggest its pathogenic role in vascular calcification associated with chronic inflammation.
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PMID:IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2. 3123 35

Emerging evidence shows that histone modification and its related regulators are involved in the progression and chemoresistance of ovarian cancer (OC) cells. Our present study found that the expression of Jumonji C domain-containing 2A (JMJD2A), while not JMJD2B or JMJD2C, is increased in OC cells and tissues as compared with that in their corresponding controls. Knockdown of JMJD2A can decrease proliferation while increase cisplatin (CDDP) sensitivity of OC cells. By screening the expression of cytokines involved in the progression of ovarian cancer, we found that knockdown of JMJD2A can inhibit the expression of interleukin-6 (IL-6) and IL-8 in ovarian cancer cells. Recombinant IL-6 (rIL-6) and rIL-8 can attenuate si-JMJD2A-suppressed malignancy of OC cells. Mechanistically, JMJD2A can directly bind with the promoter of IL-6 to trigger its transcription. For IL-8, JMJD2A can increase it mRNA stability in OC cells. Collectively, we revealed that JMJD2A can trigger the malignancy of OC cells via upregulation of IL-6 and IL-8. It suggested that JMJD2A might be a potential target for OC treatment and therapy.
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PMID:IL-6 and IL-8 are involved in JMJD2A-regulated malignancy of ovarian cancer cells. 3217 34