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Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1¹

Hyun-Mi Ko^*,, Sin-Hye Oh^*,, Hwa-Suk Bang^*,, Nam-In Kang^*,, Baik-Hwan Cho^*,, Suhn-Young Im^2,*, and Hern-Ku Lee^2,3,*,

^* Dental Science Research Institute, 2nd stage Brain Korea, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea; Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Republic of Korea; Department of Immunology, Chonbuk National University Medical School, Jeonju, Republic of Korea; and Department of Surgery and Research Institute of Clinical Medicine, Center for University-wide Research Facilities, Chonbuk National University Medical School, Jeonju, Republic of Korea

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 A₂ activity. In this study, we investigated how Gln regulates MAPK activation, as the molecular mechanism underlying Gln-induced cytosolic phospholipase A₂ 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 (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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-313-C00723).

² S.-Y.I. and H.-K.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Hern-Ku Lee, Department of Immunology, Chonbuk National University Medical School, Chonju, Chonbuk, Republic of Korea. E-mail address: leeh-k{at}chonbuk.ac.kr

⁴ Abbreviations used in this paper: Gln, L-glutamine; PLA₂, phospholipase A₂; c PLA₂, cytoplasmic PLA₂; MKP-1, MAPK phosphatase-1; PEI, polyethylene imine; siRNA, small interfering RNA; HSP, heat shock protein.