Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

The nonessential amino acid L-glutamine (Gln) is the most abundant amino acid in plasma. Clinical trials have demonstrated that Gin therapy is safe and improves clinical outcomes in critically ill patients. We have previously shown that Gin protect animals from endotoxic shock through the inhibition of cytosolic phospholipase A(2) activity. In this study, we investigated how Gin regulates MAPK activation, as the molecular mechanism underlying Gin-induced cytosolic phospholipase A2 inactivation. Gin rapidly (within 10 min) inactivated p38 and JNK, but not ERK, by dephosphorylating them only when these MAPKs were phosphorylated in response to LPS in vivo as well as in vitro. Western blot analysis revealed that Gin administration resulted in rapid (similar to 5 min) phosphorylation and protein induction of MAP kinase phosphatase-1 (MKP-1). MKP-1 siRNA abrogated the Gin-mediated a) inactivation of p38 and JNK, 2) induction of MKP-1, and 3) protection against endotoxic shock. The ERK inhibitor U0126 blocked Gin-induced MKP-1 phosphorylation and protein induction, as well as Gin's protective activity against endotoxic shock. These data suggest that Gln exerts a beneficial effect on endotoxic shock by inactivating p38 and JNK via a rapid induction of MKP-1 protein in an ERK-dependent way. The Journal of immunology, 2009, 182: 7957-7962.