ABSTRACT
Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients. However, the molecular controls of elevated body temperature are poorly understood. We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C). Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable. Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs. ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia. Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course. Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143.
Subject(s)
Feedback, Physiological , Fever/genetics , Leukocytes, Mononuclear/immunology , MicroRNAs/genetics , RNA-Binding Proteins/genetics , Body Temperature , Body Temperature Regulation/genetics , Cell Line , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/immunology , Fever/immunology , Fever/pathology , Gene Expression Profiling , Gene Expression Regulation , Humans , Interleukin-6/genetics , Interleukin-6/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Macrophages/cytology , Macrophages/immunology , MicroRNAs/immunology , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA-Binding Proteins/antagonists & inhibitors , RNA-Binding Proteins/immunology , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/immunology , Signal Transduction , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberrant miRNA expression, have consistently underpinned our understanding of the role that miRNAs play in cancer development. Here, we review the expanding roles attributed to miRNAs in the pathogenesis of different types of myeloid malignancies and highlight key findings.
