Glucocorticoid‐induced microRNA‐511 protects against TNF by down‐regulating TNFR 1

TNF is a central actor during inflammation and a well‐recognized drug target for inflammatory diseases. We found that the mouse strain SPRET /Ei, known for extreme and dominant resistance against TNF ‐induced shock, displays weak expression of TNF receptor 1 protein ( TNFR 1) but normal mRNA expression, a trait genetically linked to the major TNFR 1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR 1‐regulating miR‐511. This mi RNA is a genuine TNFR 1 regulator in cells. In mice, overexpression of miR‐511 down‐regulates TNFR 1 and protects against TNF , while anti‐miR‐511 up‐regulates TNFR 1 and sensitizes for TNF , breaking the resistance of SPRET /Ei. We found that miR‐511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR 1 modulator and thus an anti‐inflammatory miR. Since minimal reductions of TNFR 1 have considerable effects on TNF sensitivity, we believe that at least part of the anti‐inflammatory effects of glucocorti‐coids are mediated by induction of this miR, resulting in reduced TNFR 1 expression.