Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis

Huacong Chen, Hua Xu, Jiali Dong, Jing Li, Fayez K Ghishan

Research output: Contribution to journalArticle

22 Citations (Scopus)

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-α 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-α-treated cells. Transient transfection indicated that TNF-α inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF-α-mediated NaPi-IIb downregulation. Signaling transduction study and coimmunoprecipitation suggested that TNF-α 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-α through a novel molecular mechanism involving TNF-α/EGF receptor interaction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 2009

Fingerprint

Intestinal Absorption
Colitis
Tumor Necrosis Factor-alpha
Phosphates
Inflammatory Bowel Diseases
Trinitrobenzenes
Bone and Bones
Sulfonic Acids
Microvilli
Epidermal Growth Factor Receptor
Sodium-Phosphate Cotransporter Proteins
Down-Regulation
Neurofibromin 1
Caco-2 Cells
Membranes
MAP Kinase Signaling System
Enterocytes
Electrophoretic Mobility Shift Assay
Luciferases
Intestines

Keywords

  • Caco-2 cells
  • EGF receptor
  • Trinitrobenzene sulphonic acid colitis
  • Type IIb sodium-phosphate cotransporters

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis. / Chen, Huacong; Xu, Hua; Dong, Jiali; Li, Jing; Ghishan, Fayez K.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 4, 04.2009.

Research output: Contribution to journalArticle

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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-α 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-α-treated cells. Transient transfection indicated that TNF-α inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF-α-mediated NaPi-IIb downregulation. Signaling transduction study and coimmunoprecipitation suggested that TNF-α 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-α through a novel molecular mechanism involving TNF-α/EGF receptor interaction.",
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