O044 Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Introduction Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. We demonstrate the increased TNF sensitivity of mice expressing a mutant GR (GR dim / dim ), which does not dimerize or induce GRE genes. Induction of MKP-1 seems essential for GR control of TNF-induced inflammation: TNF fails to induce the MKP-1-encoding gene Dusp1 in GR dim / dim mice, and MKP-1 −/− mice are strongly sensitized to TNF. This sensitization was shown by increased inflammatory gene induction in livers, circulating cytokines, cell death in intestinal epithelium, and by severe intestinal inflammation, hypothermia and death. Because JNK phosphorylation is significantly higher in livers of MKP-1 −/− mice, JNK-deficient mice were studied for their response to TNF. Although JNK-1 −/− mice showed no change in sensitivity to TNF, JNK-2 −/− mice were significantly protected against TNF, which identifies JNK-2 as an essential player in inflammation induced in vivo by TNF. Using MKP-1/JNK-2 and GR dim / dim /JNK-2 double deficient mice, which are significantly less sensitive to TNF than MKP-1 −/− and GR dim / dim mice, respectively, we provide evidence that the increased sensitivity of MKP-1 −/− and GR dim / dim mice to TNF is partly due JNK-2. Our data show that dimerization of GR critically induces MKP-1 and hence controls JNK-2, an essential mediator of TNF-induced apoptosis and lethal inflammation.