Identification of Rab6a as a New Target of microRNA-155 Involved in Regulating Lipopolysaccharide-Induced TNF Secretion
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Identification of Rab6a as a New Target of microRNA-155 Involved in Regulating Lipopolysaccharide-Induced TNF Secretion Yang Yang1 and Lixia Yang1,2,3
Abstract—This study aims to provide experimental proof that Rab6a is an efficient target of microRNA155 in regulating pro-inflammatory tumor necrosis factor (TNF) secretion stimulated by lipopolysaccharide (LPS) in macrophages. We identified Rab6a as a new target of microRNA-155 (miR-155) and found that overexpression of miR-155 decreased Rab6a expression at both protein and mRNA levels, which resulted in a significant reduction of TNF secretion induced by lipopolysaccharide stimulation. We have demonstrated that miR-155 can negatively regulate inflammatory TNF secretion in lipopolysaccharide stimulated macrophages, partly by targeting Rab6a, thereby providing new insights into the role of miR-155 in cytokine secretion in inflammatory macrophages. KEY WORDS: microRNA-155; Rab6a; inflammatory TNF; LPS.
INTRODUCTION MicroRNAs (MiRNAs) are known to regulate gene expression post-transcriptionally by triggering either translation repression or RNA degradation [1]. Recent studies have revealed their indispensable roles in inflammation and immune responses and in controlling certain chronic inflammatory diseases [2]. MicroRNA-155 (miR-155) is highly expressed in activated macrophages, monocytes, and some other immune cells [3, 4]. Lipopolysaccharide (LPS), a component of Gram-negative bacteria, effectively activates and stimulates macrophages to secrete the tumor necrosis factor alpha (TNF-α), which is a potent multifunctional cytokine. TNF and other inflammatory cytokines are involved in inflammatory diseases and are important clinical therapeutic targets [5]. TNF is trafficked through the Golgi to recycling endosomes and then to filopodia and phagocytic cups at the cell surface for cleavage and release [6]. Rab GTPases that mediate membrane traffic have been identified as 1
Department of Postgraduate, Third Military Medical University, Chongqing, 400038, China 2 Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, 650032, China 3 To whom correspondence should be addressed at Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, 650032, China. E-mail: [email protected]
regulators of TNF secretion in macrophages [7, 8]. The Golgi complex is necessary for the transport of several secreted cytokines, and Rab6 is the quintessential and most abundant Golgi-associated Rab protein [9]. Micaroni et al. reported Rab6a/a′ to be an important Golgi regulator of TNF secretion in macrophages [10]. We further noticed that Rab6a is one of the potential targets of miR-155. Hence, in this study, we explored the effect of miR-155 on Rab6a and searched for additional mechanisms through which miR-155 affects LPS-induced inflammation in macrophages.
MATERIALS AND METHODS Cell Culture The mouse macrophage cell-line RAW264.7 was maintained in DMEM supplemented with 10 % fetal bovine plasma (Sigma, USA), at 37 °C in a 5 % CO2 i
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