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Am J Physiol Gastrointest Liver Physiol 296: G775-G781, 2009. First published February 5, 2009; doi:10.1152/ajpgi.90722.2008
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MUCOSAL BIOLOGY

Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis

Huacong Chen,1,2,* Hua Xu,1,* Jiali Dong,1 Jing Li,1 and Fayez K. Ghishan1

1University of Arizona Health Sciences Center, Tucson, Arizona; 2Wellesley College, Wellesley, Massachusetts

Submitted 26 December 2008 ; accepted in final form 4 February 2009

Phosphate homeostasis is critical for many physiological functions. Up to 85% of phosphate is stored in bone and teeth. The remaining 15% is distributed in cells. Phosphate absorption across the brush-border membrane (BBM) of enterocytes occurs mainly via a sodium-dependent pathway, which is mediated by type IIb sodium-phosphate cotransporters (NaPi-IIb). Patients of inflammatory bowel diseases (IBDs) suffer not only from diarrhea and nutrient malabsorption but also from bone loss. About 31–59% of patients with IBD develop bone disorders. Since the intestine is a primary location for dietary phosphate absorption, it is logical to postulate that there is an inverse relationship between gastrointestinal disorders and phosphate transport, which, in turn, contributes to bone disorders observed in patients with IBD. Phosphate absorption and NaPi-IIb expression was studied with BBM vesicles isolated from trinitrobenzene sulphonic acid (TNBS) animals as well as in Caco-2 cells. The mechanism of TNF-{alpha} downregulation of NaPi-IIb expression was investigated by luciferase assay, gel mobility shift assay (GMSA), and coimmunoprecipitation. Intestinal phosphate absorption mediated by NaPi-IIb was reduced both in TNBS colitis and in TNF-{alpha}-treated cells. Transient transfection indicated that TNF-{alpha} inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF-{alpha}-mediated NaPi-IIb downregulation. Signaling transduction study and coimmunoprecipitation suggested that TNF-{alpha} interacts with EGF receptor to activate ERK1/2 pathway. Intestinal phosphate absorption mediated by NaPi-IIb protein is reduced in colitis. This inhibition is mediated by the proinflammatory cytokine TNF-{alpha} through a novel molecular mechanism involving TNF-{alpha}/EGF receptor interaction.

trinitrobenzene sulphonic acid colitis; Caco-2 cells; type IIb sodium-phosphate cotransporters; EGF receptor


Address for reprint requests and other correspondence: F. Ghishan, Professor and Head, Dept. of Pediatrics, Steele Children's Research Ctr., Univ. of Arizona Health Sciences Ctr., 1501 N. Campbell Ave., Tucson, AZ 85724 (e-mail: fghishan{at}peds.arizona.edu)






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