title: Keratinocyte growth factor-2 stimulates P-glycoprotein expression and function in intestinal epithelial cells.
abstract: Intestinal P-glycoprotein (Pgp/multidrug resistance 1), encoded by the ATP-binding cassette B1 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 using Caco-2 cells. Short-term treatment of Caco-2 cells with KGF2 (10 ng/ml, 1 h) 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. The specific fibroblast growth factor receptor (FGFR) antagonist PD-161570 blocked the KGF2-mediated increase in Pgp activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 attenuated the stimulatory effects of KGF2 on Pgp activity. Small-interfering RNA knockdown of Erk1/2 MAPK blocked the increase in surface Pgp levels by KGF2. Long-term treatment with KGF2 (10 ng/ml, 24 h) 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 the Erk1/2 MAPK pathway. In conclusion, our findings define the posttranslational 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.
authors: Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. saksena@uic.edu
authors: Seema
authors: S
authors: Saksena
authors: Shubha
authors: S
authors: Priyamvada
authors: Anoop
authors: A
authors: Kumar
authors: Maria
authors: M
authors: Akhtar
authors: Vikas
authors: V
authors: Soni
authors: Arivarasu Natarajan
authors: AN
authors: Anbazhagan
authors: Anas
authors: A
authors: Alakkam
authors: Waddah A
authors: WA
authors: Alrefai
authors: Pradeep K
authors: PK
authors: Dudeja
authors: Ravinder K
authors: RK
authors: Gill
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation / Q000502:physiology; D018938:Caco-2 Cells; D004077:Digoxin / Q000494:pharmacology; D042783:Endothelial Cells / Q000502:physiology*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D051526:Fibroblast Growth Factor 10; D005419:Flavonoids; C107527:PD 161570; D011743:Pyrimidines; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D004077:Digoxin; D014508:Urea; D014700:Verapamil; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one