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* Mucosal Immunity Laboratory, Department of Human Morphology, Università degli Studi di Milano, Milan, Italy;
Institute of Pathology, Università degli Studi di Milano, Milan, Italy; and
Molecular Targeting Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
In this study, we demonstrate the protective effect of the activation of sodium-dependent glucose transporter-1 (SGLT-1) on damages induced by TLR ligands, in intestinal epithelial cells and in a murine model of septic shock. In intestinal epithelial cell lines, glucose inhibited the IL-8/keratinocyte-derived chemokine production and the activation of the TLR-related transcription factor NF-
B stimulated by LPS or CpG-oligodeoxynucleotide. Oral ingestion of glucose was found to protect 100% of mice from lethal endotoxic shock induced by i.p. LPS administration; protection was only observed when glucose was administered orally, not by i.p. route, suggesting the important role of intestinal epithelial cells in this protection. In addition, we observed that the in vivo protection depends on an increase of anti-inflammatory cytokine IL-10. The cornerstone of the observed immunomodulatory and life-saving effects resides in activation of SGLT-1; in fact, the glucose analog 3-O-methyl-D-gluco-pyranose, which induces the transporter activity, but is not metabolized, exerted the same inhibitory effects as glucose both in vitro and in vivo. Thus, we propose that activated SGLT-1, apart from its classical metabolic function, may be a promising target for inhibition of bacteria-induced inflammatory processes and life-saving treatments, assuming a novel role as an immunological player.
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 partially supported by Associazione Italiana per la Ricerca sul Cancro.
2 M.P. and S.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Cristiano Rumio, Department of Human Morphology, Faculty of Pharmacy, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy. E-mail address: cristiano.rumio{at}unimi.it
4 Abbreviations used in this paper: IEC, intestinal epithelial cell; 3-OMG, 3-O-methyl-D-gluco-pyranose; GalN, D+-galactosamine hydrochloride; KC, keratinocyte-derived chemokine; ODN, oligodeoxynucleotide; os, oral route; SGLT, sodium-dependent glucose transporter; siRNA, small interfering RNA.
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  L. Zanobbio, M. Palazzo, S. Gariboldi, G. F. Dusio, D. Cardani, V. Mauro, F. Marcucci, A. Balsari, and C. Rumio Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and D-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice Am. J. Pathol., September 1, 2009; 175(3): 1066 - 1076. [Abstract] [Full Text] [PDF]
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