MicroRNA-532-3p Regulates Pro-Inflammatory Human THP-1 Macrophages by Targeting ASK1/p38 MAPK Pathway
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ORIGINAL ARTICLE
MicroRNA-532-3p Regulates Pro-Inflammatory Human THP-1 Macrophages by Targeting ASK1/p38 MAPK Pathway Palani Dinesh,1 Sowmiya Kalaiselvan,1 Sali Sujitha,1 and Mahaboobkhan Rasool
1,2
(Received March 24, 2020; accepted August 18, 2020)
Inflammation is a complex biological process which alters the normal physiological function of the immune system resulting in an abnormal microenvironment that leads to several clinical complications. The process of inflammation is mediated through various intracellular signaling factors inside the cells. Apoptosis signal–regulating kinase 1 (ASK1) is an inflammation-derived kinase that controls the activation of other family of kinases such as p38 mitogen–activated protein kinases (p38 MAPKs), which mediates various the inflammatory processes. In this study, we cultured THP-1 macrophage cells to undergo inflammatory proliferation with LPS (1 μg/ml) and TNFα (10 ng/ml) stimulation. Initial in silico analysis was utilized to predict novel microRNAs (miRNAs) that target ASK1 signaling and its expression levels in LPS and TNFα stimulated THP-1 cells were estimated. Among the miRNAs, miR-532-3p showcased the highest binding affinity towards ASK1 kinase. We witnessed that transient transfection of miR-532-3p diminished the levels of ASK1 and downstream phosphorylation/translocation of p38 MAPK. Furthermore, direct targeting of ASK1 resulted in regulation of uncontrolled release of cytokines (TNFα, IL-6, and IL-23) and chemokines (GM-CSF and MIP-2α). Overall, we suggest that miR-532-3p attenuates the pro-inflammatory nature of macrophages by targeting ASK1/p38 MAPK signaling pathway and can be used as a molecular intervention for treating inflammatory diseases. Abstract—
KEY WORDS: inflammation; pre-miRNAs; miR-532-3p; ASK1; p38 MAPKs.
INTRODUCTION Palani Dinesh and Sowmiya Kalaiselvan contributed equally to this work. 1
SMV 240, Immunopathology Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore Tamil Nadu 632 014 India 2 To whom correspondence should be addressed at SMV 240, Immunopathology Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore Tamil Nadu 632 014 India. E-mail: [email protected]
Inflammation is an intricate phenomenon that renders to a localized accumulation of different subsets of immunes cells caused due to microbial infestation, injury, chemical ingestion, and lipopolysaccharide (LPS) endotoxin [1, 2]. LPS from microbial origin has been designated to be the key player in initiating various inflammatory disease
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Dinesh, Kalaiselvan, Sujitha, and Rasool processes including redness, swelling, and recruitment of immune cells to the site of infection [3–5]. LPS found on the outer surface of microbes are generally recognized by the TLR family of receptors expressed majorly in the macrophage population circulating at the site of infection [6]. Macrophages being the sentinels of the immune syste
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