Negative feedback loop of ERK/CREB/miR‐212‐3p inhibits HBeAg‐induced macrophage activation

Abstract

The activation of liver macrophages is closely related to liver injury after HBV infection. Our previous results demonstrated that HBeAg played a key role in inducing macrophage activation. As we all know, miRNAs are involved in the regulation of multiple immune cell functions. Meanwhile, we have shown that miR‐155 positively regulates HBeAg‐induced macrophage activation and accelerates liver injury. Subsequently, based on our previous miRNA sequencing results, we further evaluated the role of miR‐212‐3p called ‘neurimmiR’ in HBeAg‐induced macrophages in this study. First, miR‐212‐3p expression was significantly elevated in HBeAg‐treated macrophages. Meanwhile, we found up‐regulation of miR‐212‐3p significantly decreased the production of cytokines, whereas knockdown of miR‐212‐3p held the opposite effect by gains and losses of function. Mechanically, although MAPK signal pathway, including ERK, JNK and p38, was activated in HBeAg‐induced macrophages, only ERK promoted the expression of miR‐212‐3p via transcription factor CREB, which was able to bind to the promoter of miR‐212‐3p verified by ChIP assay. Moreover, we further indicated that up‐regulated miR‐212‐3p inhibited HBeAg‐induced inflammatory cytokine production through targeting MAPK1. In conclusion, miR‐212‐3p was augmented in HBeAg‐stimulated macrophages via ERK/CREB signal pathway and the elevated miR‐212‐3p suppressed inflammatory cytokine production induced by HBeAg through targeting MAPK1.

The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis

“…The immune responses triggered by HBcAg are illustrated in Figure 2. However, in our previous research, we found HBcAg could not effectively induce macrophage activation and participated in the liver damage caused by it (49)(50)(51). Therefore, HBcAg is a multifunctional protein, it is not only involved in viral nucleocapsid formation, but also associated with cccDNA epigenetic modulation and HBV immune evasion.…”

MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents

“…So far, only limited upstream regulators for miR-212-5p expression have been identified. 27 , 28 , 29 While a recent study showed that miR-212-5p was upregulated by hypoxia-inducible factor-1α (HIF-1α) in pancreatic cancer cells in hypoxia, 29 we do not know if HIF-1α mediates the upregulation of miR-212-5p in PASMCs in human PAH patients or rodents with PH, as the regulation of gene expression is always cell-type, tissue-type, and disease-background dependent. The cAMP-responsive transcription factor (CREB) has been recently identified as another transcriptional regulator for miR-212 in neuron cells, macrophages, or insulin-secreting β-cells.…”

“…The cAMP-responsive transcription factor (CREB) has been recently identified as another transcriptional regulator for miR-212 in neuron cells, macrophages, or insulin-secreting β-cells. 27 , 28 , 30 Recent studies showed that an extracellular cyclic AMP (cAMP)/CREB signaling in pulmonary arteries (including both smooth muscle and endothelial cells on the vessels) is activated to mitigate the severity of pulmonary vascular remodeling and PH 31 and that SMC-specific knockout of CREB induced pulmonary vessel wall thickening and PH in mice. 32 These findings not only revealed a protective mechanism that is activated during the pathogenesis of PH, but also led to our speculation that miR-212-5p is upregulated by CREB in PASMCs to play the protective role in PH.…”

Decreased interferon regulatory factor 6 expression due to DNA hypermethylation predicts an unfavorable prognosis in clear cell renal cell carcinoma

“…Furthermore, we performed gene set enrichment analysis (GSEA) of the IRF6 high and low expression groups to study the potential molecular mechanism of IRF6. The results showed that MAPK, ERBB, ERK and CREB pathways, which play important roles in the regulation of immune cells in the tumor environment [19][20][21][22], were significantly activated in the IRF6 high expression group (Figure 9). Thus, the above results demonstrated that the decrease of IRF6 expression was related to the alterations of tumor immune cells infiltration, which might affect the prognosis of ccRCC patients.…”