MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1(-/-) macrophages exhibited increased responsiveness to LPS in culture and Akt1(-/-) mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1(-/-) macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.

A. Androulidaki A*, Iliopoulos D*, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31:220-31, 2009. *equal contribution

This was one of the first studies showing that microRNAs regulating the expression of essential inflammatory molecules. Specifically, we found that let-7e microRNA regulates the expression of Toll-like Receptor 4 (TLR4) and miR-155 regulates the expression of SOCS1.

B. Iliopoulos D, Kavousanaki M, Ioannou M, Boumpas D, Verginis P. The negative costimulatory molecular PD-1 modulates the balance between immunity and tolerance via miR-21. Eur J Immunol 41:1754-63, 2011.

C. Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen P, Kobayashi KS. NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci USA, 107:13794-9,