title: Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis.
abstract: 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.
authors.affiliation: Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
authors.forename: Huacong
authors.initials: H
authors.lastname: Chen
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Jiali
authors.initials: J
authors.lastname: Dong
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Fayez K
authors.initials: FK
authors.lastname: Ghishan
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010710:Phosphates / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D010710:Phosphates; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D014302:Trinitrobenzenesulfonic Acid; D004247:DNA; D066246:ErbB Receptors