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 Blood, 1 December 2008, Vol. 112, No. 12, pp. 4591-4597.
Prepublished online as a Blood First Edition Paper on September 12, 2008; DOI 10.1182/blood-2008-04-152488.

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IMMUNOBIOLOGY

Suppression of LPS-induced Interferon-{gamma} and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation

Rujuan Dai1, Rebecca A. Phillips1,*, Yan Zhang2,*, Deena Khan1, Oswald Crasta2, and S. Ansar Ahmed1

1 Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathology, Virginia-Maryland Regional College of Veterinary Medicine, and 2 Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg

MicroRNAs (miRNAs), recently identified noncoding small RNAs, are emerging as key regulators in homeostasis of the immune system. Therefore, aberrant expression of miRNAs may be linked to immune dysfunction, such as in chronic inflammation and autoimmunity. In this study, we investigated the potential role of miRNAs in estrogen-mediated regulation of innate immune responses, as indicated by up-regulation of lipopolysaccharide (LPS)–induced interferon-gamma (IFN{gamma}), inducible nitric oxide synthase (iNOS), and nitric oxide in splenic lymphocytes from estrogen-treated mice. We found that miR-146a, a negative regulator of Toll-like receptor (TLR) signaling, was decreased in freshly isolated splenic lymphocytes from estrogen-treated mice compared with placebo controls. Increasing the activity of miR-146a significantly inhibited LPS-induced IFN{gamma} and iNOS expression in mouse splenic lymphocytes. Further, miRNA microarray and real-time reverse transcriptase–polymerase chain reaction (RT-PCR) analysis revealed that estrogen selectively up-regulates/down-regulates the expression of miRNAs in mouse splenic lymphocytes. miR-223, which is markedly enhanced by estrogen, regulates LPS-induced IFN{gamma}, but not iNOS or nitric oxide in splenic lymphocytes. Inhibition of miR-223 activity decreased LPS-induced IFN{gamma} in splenic lymphocytes from estrogen-treated mice. Our data are the first to demonstrate the selective regulation of miRNA expression in immune cells by estrogen and are indicative of an important role of miRNAs in estrogen-mediated immune regulation.


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