MiR-155 Induction by Microbes/Microbial Ligands Requires NF-κB-Dependent de novo Protein Synthesis

Filgueiras

The Journal of Immunology

et al. 2014

MicroRNAs are known to control Toll like receptor activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. Here, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Gαi signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to AP-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both WT and LT-deficient macrophages. Together, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs which regulate MyD88-dependent activation of macrophages.

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Enhances the Generation of Proinflammatory MicroRNAs To Promote MyD88-Dependent Macrophage Activation

Filgueiras

The Journal of Immunology

et al. 2014

“…miRNAs regulate intracellular pathways of numerous inflammatory mediators [16] and their role in the regulation of immune responses has been widely documented, including the presence of miR-181a in the thymus and miR-223 in the bone marrow being implicated in the differentiation of pluripotent hematopoietic stem cells [17,18]. Additionally, miR-155 has been shown to be induced by viral and bacterial pathogens, as well as inflammatory cytokines, suggesting it to be a component of the innate immune response [19,20]. Even though the function of these novel regulators in several processes is now well described, their effect on the JAK-STAT pathway has not been explored in any great detail.…”

Section: Introductionmentioning

confidence: 99%

miR-19a: An Effective Regulator of SOCS3 and Enhancer of JAK-STAT Signalling

et al. 2013

Suppressors of cytokine signalling (SOCS) proteins are classic inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Many cytokines and pathogenic mediators induce expression of SOCS, which act in a negative feedback loop to inhibit further signal transduction. SOCS mRNA expression is regulated by DNA binding of STAT proteins, however, their post-transcriptional regulation is poorly understood. microRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences on target mRNAs, often silencing gene expression. miR-19a has been shown to regulate SOCS1 expression during mutiple myeloma and be induced by the anti-viral cytokine interferon-(IFN)-α, suggesting a role in the regulation of the JAK-STAT pathway. This study aimed to identify targets of miR-19a in the JAK-STAT pathway and elucidate the functional consequences. Bioinformatic analysis identified highly conserved 3’UTR miR-19a target sequences in several JAK-STAT associated genes, including SOCS1, SOCS3, SOCS5 and Cullin (Cul) 5. Functional studies revealed that miR-19a significantly decreased SOCS3 mRNA and protein, while a miR-19a antagomir specifically reversed its inhibitory effect. Furthermore, miR-19a-mediated reduction of SOCS3 enhanced IFN-α and interleukin (IL)-6 signal transduction through STAT3. These results reveal a novel mechanism by which miR-19a may augment JAK-STAT signal transduction via control of SOCS3 expression and are fundamental to the understanding of inflammatory regulation.

“…Among several inflammatory and oncogenic microRNAs, microRNA-155 (miR-155) has been recently identified as an NF-κB-dependent microRNA, involving in the development of inflammation, immune responses, and cancers [5,6,11,25]. In this context, Wang et al have reported both miR-155 overexpression and NF-кB activation at the early stages of choline-deficient and amino acid-defined diet-induced hepatocarcinogenesis mouse model [27].…”

mentioning

confidence: 99%

A signature of microRNA-155 in the pathogenesis of diabetic complications

et al. 2015

The current study was designed to explore the potential involvement of miR-155 in the pathogenesis of diabetes complications. Male rats were divided into control and diabetic groups (n = 6). Type 2 diabetes was induced by a single-dose injection of nicotinamide (110 mg/kg; intraperitoneal (i.p.)), 15 min before injection of streptozotocin (STZ; 50 mg/kg; i.p.) in 12-h fasted rats. Two months after induction of diabetes, the rats were sacrificed for subsequent measurements. The nuclear factor kappa B (NF-κB) activity was higher in diabetic peripheral blood mononuclear cells (PBMCs), aorta, heart, kidney, liver, and sciatic nerve, than the control counterparts. Also, apoptosis rate was increased in these tissues, except the aorta. NF-κB messenger RNA (mRNA) expression level was higher in the kidney, heart, PBMCs, and sciatic nerve of diabetic rats than their control counterparts. Except the liver, the miR-155 expression level was significantly decreased in diabetic kidney, heart, aorta, PBMCs, and sciatic nerve versus the controls. Moreover, the expression of miR-155 was negatively correlated with NF-κB activity and apoptosis rate. These results suggest that changes in the expression of miR-155 may participate in the pathogenesis of diabetes-related complications, but causal relationship between miR-155 dysregulation and diabetic complications is unknown.