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 Gln therapy is safe and improves clinical outcomes in critically ill patients. We have previously shown that Gln protect animals from endotoxic shock through the inhibition of cytosolic phospholipase A(2) activity. In this study, we investigated how Gln regulates MAPK activation, as the molecular mechanism underlying Gln-induced cytosolic phospholipase A(2) inactivation. Gln 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 Gln administration resulted in rapid ( approximately 5 min) phosphorylation and protein induction of MAP kinase phosphatase-1 (MKP-1). MKP-1 siRNA abrogated the Gln-mediated 1) inactivation of p38 and JNK, 2) induction of MKP-1, and 3) protection against endotoxic shock. The ERK inhibitor U0126 blocked Gln-induced MKP-1 phosphorylation and protein induction, as well as Gln'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.
Ko
Hyun-Mi
HM
Dental Science Research Institute, 2nd stage Brain Korea, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
Oh
Sin-Hye
SH
Bang
Hwa-Suk
HS
Kang
Nam-In
NI
Cho
Baik-Hwan
BH
Im
Suhn-Young
SY
Lee
Hern-Ku
HK
D000818:Animals; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005973:Glutamine / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D012772:Shock, Septic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D015996:Survival Rate; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D005973:Glutamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1