%0 Journal Article
%T Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets
%A Valia Bravo-Egana
%A Samuel Rosero
%A Dagmar Klein
%A Zhijie Jiang
%A Nancy Vargas
%A Nicholas Tsinoremas
%A Marco Doni
%A Michele Podetta
%A Camillo Ricordi
%A R. Damaris Molano
%A Antonello Pileggi
%A Ricardo L. Pastori
%J Journal of Transplantation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/723614
%X Nonspecific inflammation in the transplant microenvironment results in ¦Â-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposed in vitro to proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation both in vivo and in vitro. Induction of miRNAs was dependent on NF-¦ÊB, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies of ¦Â-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca2+ sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions. 1. Introduction Inflammation involves both the innate and adaptive immune systems following infection or injury. Deregulation of this process leads to chronic inflammation, generating a pathological response that favors destruction of the tissue involved [1]. Inflammation is the common denominator of several pathological conditions, including type 1 and type 2 diabetes. It also contributes to immune rejection in transplantation. A plethora of proinflammatory mediators has been associated with toxicity and impairment of ¦Â-cell function [2], including cytokines [3¨C6], hyperglycemia, and hyperlipidemia [7¨C9]. Inflammation plays key roles in islet engraftment and survival after transplantation. During the early posttransplant period, islet cells are exposed to noxious stimuli, activation of macrophages, local secretion of chemokines, tissue factor induction, and formation of reactive oxygen species (ROS) due to hypoxic conditions, all causing an impairment of engraftment and function [10¨C12]. The nonspecific inflammation generated in the transplant microenvironment triggers adaptive immune responses, negatively influencing graft survival [13, 14]. Emerging
%U http://www.hindawi.com/journals/jtrans/2012/723614/