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IL-1?-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXR?, or PPAR? 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-?, IFN-?, and IL-1?, and analysing PDZK1 promotor activity, mRNA and protein expression. Results: IL-1? 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-1?-responsiveness. This region harbors the retinoid acid response element RARE as well as binding sites for transcription factors involved in IL-? downstream signaling. ERK1/2 inhibition by the specific MEK1/2 inhibitors PD98059/U0126 significantly attenuated the IL-1? mediated downregulation of PDZK1, while NF-?B, p38 MAPK, and JNK inhibition did not. Expression of the nuclear receptors RXR? and PPAR? was decreased in inflamed colonic-mucosa of ulcerative colitis patients and in IL-1?-treated Caco2-BBE cells. Moreover, the RAR/RXR ligand 9-cis retinoic acid and the PPAR?-agonist GW7647 stimulated PDZK1 mRNA and protein expression and attenuated IL-1?-mediated inhibition. Conclusions: The strong decrease in PDZK1 expression during intestinal inflammation may be in part a consequence of IL-1?-mediated RXR? and PPAR? 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.

SUBMITTER: Luo M

PROVIDER: S-EPMC5293818 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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IL-1β-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXRα, or PPARα Stimulation in Enterocytes.

Luo Min M Yeruva Sunil S Liu Yongjian Y Chodisetti Giriprakash G Riederer Brigitte B Menon Manoj B MB Tachibana Keisuke K Doi Takefumi T Seidler Ursula E UE

Frontiers in physiology 20170207

<b>Background:</b> 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. <b>Aim and Methods:</b> 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 PDZ ...[more]

PMID: 28223944

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Project description:BackgroundImpaired salt and water absorption is an important feature in the pathogenesis of diarrhea in inflammatory bowel disease (IBD). We analyzed the expression of proinflammatory cytokines in the infiltrating immune cells and the function and expression of the Na(+)/H(+) exchanger isoform 3 (NHE3) and its regulatory PDZ-adaptor proteins NHERF1, NHERF2, and PDZK1 in the colon of interleukin-10-deficient (IL-10(-/-)) mice.Methodology/principal findingsGene and protein expression were analyzed by real-time reverse transcription polymerase chain reaction (qRT-PCR), in situ RT-PCR, and immunohistochemistry. NHE3 activity was measured fluorometrically in apical enterocytes within isolated colonic crypts. Mice developed chronic colitis characterized by a typical immune cell infiltration composed of T-lymphocytes and macrophages, with high levels of gene and protein expression of the proinflammatory cytokines interleukin-1? and tumor necrosis factor-?. In parallel, inducible nitric oxide synthase expression was increased while procaspase 3 expression was unaffected. Interferon-? expression remained low. Although acid-activated NHE3 activity was significantly decreased, the inflammatory process did not affect its gene and protein expression or its abundance and localization in the apical membrane. However, expression of the PDZ-adaptor proteins NHERF2 and PDZK1 was downregulated. NHERF1 expression was unchanged. In a comparative analysis we observed the PDZK1 downregulation also in the DSS (dextran sulphate sodium) model of colitis.Conclusions/significanceThe impairment of the absorptive function of the inflamed colon in the IL-10(-/-) mouse, in spite of unaltered NHE3 expression and localization, is accompanied by the downregulation of the NHE3-regulatory PDZ adaptors NHERF2 and PDZK1. We propose that the downregulation of PDZ-adaptor proteins may be an important factor leading to NHE3 dysfunction and diarrhea in the course of the cytokine-mediated inflammatory process in these animal models of IBD.

Dataset Information

IL-1?-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXR?, or PPAR? Stimulation in Enterocytes.

Publications

IL-1β-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXRα, or PPARα Stimulation in Enterocytes.

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