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Keratinocyte Growth Factor-2 Stimulates P-glycoprotein Expression and Function in Intestinal Epithelial Cells.


Am J Physiol Gastrointest Liver Physiol. 2013 Jan 17;


Authors: Saksena S, Priyamvada S, Kumar A, Akhtar M, Soni V, Anbazhagan AN, Alakkam A, Alrefai WA, Dudeja PK, Gill RK


Abstract

Intestinal P-glycoprotein (P-gp/MDR1), encoded by the ATP-binding cassette B1 (ABCB1) gene, is primarily involved in the transepithelial efflux of toxic metabolites and xenobiotics from the mucosa into the gut lumen. Reduced Pgp function and expression has been shown to be associated with intestinal inflammatory disorders. Keratinocyte growth factor-2 (KGF2) has emerged as a potential target for modulation of intestinal inflammation and maintenance of gut mucosal integrity. Whether KGF2 directly regulates Pgp in the human intestine is not known. Therefore, the present studies were undertaken to determine the modulation of Pgp by KGF2 utilizing Caco-2 cells. Short-term treatment of Caco2 cells with KGF2 (10 ng/ml, 1h) increased Pgp activity (~2 fold, P<0.05) as measured by verapamil-sensitive (3)H-Digoxin flux. This increase in Pgp function was associated with an increase in surface Pgp levels. Specific fibroblast growth factor receptor (FGFR) antagonist, PD161570 blocked KGF2-mediated increase in Pgp activity. Inhibition of MAP kinase pathway by PD98059 attenuated the stimulatory effects of KGF2 on Pgp activity. siRNA knockdown of Erk1/2 MAPK blocked the increase in surface Pgp levels by KGF2. Long-term treatment with KGF2 (10 ng/ml, 24h) also significantly increased PgP activity, mRNA, protein expression and promoter activity. The long-term effects of KGF2 on Pgp promoter activity were also blocked by the FGFR antagonist and mediated by Erk1/2 MAPK pathway. In conclusion, our findings define the post-translational and transcriptional mechanisms underlying stimulation of Pgp function and expression by KGF2 that may contribute to the beneficial effects of KGF2 in intestinal inflammatory disorders.

PMID: 23328208 [PubMed - as supplied by publisher]