title: IL-1β-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXRα, or PPARα Stimulation in Enterocytes.
abstract: Background:The PDZ adaptor protein PDZK1 modulates the membrane expression and function of a variety of intestinal receptors and ion/nutrient transporters. Its expression is strongly decreased in inflamed intestinal mucosa of mice and IBD patients.Aim and Methods:We investigated whether the inflammation-associated PDZK1 downregulation is a direct consequence of proinflammatory cytokine release by treating intestinal Caco-2BBE cells with TNF-α, IFN-γ, and IL-1β, and analysing PDZK1 promotor activity, mRNA and protein expression.Results:IL-1β was found to significantly decrease PDZK1 promoter activity, mRNA and protein expression in Caco-2BBE cells. A distal region of the hPDZK1 promoter was identified to be important for basal expression and IL-1β-responsiveness. This region harbors the retinoid acid response element RARE as well as binding sites for transcription factors involved in IL-β downstream signaling. ERK1/2 inhibition by the specific MEK1/2 inhibitors PD98059/U0126 significantly attenuated the IL-1β mediated downregulation of PDZK1, while NF-κB, p38 MAPK, and JNK inhibition did not. Expression of the nuclear receptors RXRα and PPARα was decreased in inflamed colonic-mucosa of ulcerative colitis patients and in IL-1β-treated Caco2-BBE cells. Moreover, the RAR/RXR ligand 9-cis retinoic acid and the PPARα-agonist GW7647 stimulated PDZK1 mRNA and protein expression and attenuated IL-1β-mediated inhibition.Conclusions:The strong decrease in PDZK1 expression during intestinal inflammation may be in part a consequence of IL-1β-mediated RXRα and PPARα repression and can be attenuated by agonists for either nuclear receptor, or by ERK1/2 inhibition. The negative consequences of inflammation-induced PDZK1 downregulation on epithelial transport-function may thus be amenable to pharmacological therapy.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical SchoolHannover, Germany; Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical UniversityChongqing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Hannover, Germany.
authors.forename: Sunil
authors.initials: S
authors.lastname: Yeruva
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical SchoolHannover, Germany; Department of Endocrinology, the Second Affiliated Hospital of Chongqing Medical UniversityChongqing, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Hannover, Germany.
authors.forename: Giriprakash
authors.initials: G
authors.lastname: Chodisetti
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.affiliation: Department of Biochemistry, Hannover Medical School Hannover, Germany.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.affiliation: Laboratory of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Osaka University Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tachibana
authors.affiliation: Laboratory of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Osaka University Osaka, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Hannover, Germany.
authors.forename: Ursula E
authors.initials: UE
authors.lastname: Seidler
keywords: MAP kinase; PDZ adaptor protein; electrolyte transport; intestinal inflammation