Interferon-γ Down-regulates Adenosine 2b Receptor-mediated Signaling and Short Circuit Current in the Intestinal Epithelia by Inhibiting the Expression of Adenylate Cyclase

Kolachala, Vasantha L.; Asamoah, Vivian; Wang, Lixin; Srinivasan, Shanthi; Merlin, Didier; Sitaraman, Shanthi V.

doi:10.1074/jbc.m409577200

Cited by 34 publications

(34 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with these data, immunohistological studies have found decreased AC5/6 expression in surface, compared with crypt, epithelial cells in the murine colon (27), and biochemical studies have detected diminished total AC activity in differentiated villus cells compared with undifferentiated crypt epithelial cells (36). These results, along with those observed in interferon-␥-stimulated colon epithelial cells (26), indicate that AC isoform expression is dynamic and responsive to environmental cues. Importantly, the nature of the environmental stimulus determines the specificity of the AC isoform expression.…”

Section: Discussionsupporting

confidence: 60%

“…For example, interferon-␥ inhibits the expression of AC5 and AC7 and decreases cAMP synthesis (26). However, the impact of epithelial cell differentiation on AC isoform expression is not known.…”

mentioning

confidence: 99%

“…Intestinal epithelial cells express AC isoforms that can be regulated by cytokines and nitric oxide (26,27). For example, interferon-␥ inhibits the expression of AC5 and AC7 and decreases cAMP synthesis (26).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Coordinate Down-regulation of Adenylyl Cyclase Isoforms and the Stimulatory G Protein (Gs) in Intestinal Epithelial Cell Differentiation

Choi

Jeníková

Hanson

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The intestinal epithelium is dynamic, with proliferation of undifferentiated crypt cells balanced by terminal differentiation and cell death at the colon surface or small intestinal villus tips. Cyclic AMP, induced by agonists such as prostaglandin E 2 and vasoactive intestinal polypeptide, promotes proliferation and ion secretion and suppresses apoptosis in intestinal epithelial cells. Here, we show that cell differentiation in a model intestinal epithelium leads to attenuation of cAMP production in response to G protein-coupled receptor and receptor-independent agonists. Concomitantly, key components of the cAMP cascade, the ␣ subunit of the stimulatory G protein, G s , and adenylyl cyclase (AC) isoforms 3, 4, 6, and 7 are down-regulated. By contrast, AC1, AC2, AC8, and AC9, and the receptors for prostaglandin E 2 and vasoactive intestinal polypeptide, are not expressed or not affected by differentiation. We confirmed key findings in normal murine colon epithelium, in which the major AC isoforms and G s ␣ are markedly down-regulated in differentiated surface cells. Suppression of AC isoforms and G s ␣ is functionally important, because their constitutive expression completely reverses differentiation-induced cAMP attenuation. Thus, down-regulation of AC isoforms and G s ␣ is an integral part of the intestinal epithelial differentiation program, perhaps serving to release cells from cAMP-promoted anti-apoptosis as a prerequisite for cell death upon terminal differentiation.The intestinal epithelium, a single-cell layer that separates and protects the body from microbes and toxins in the intestinal lumen, is critical for digestion and uptake of nutrients and is characterized by rapid turnover and spatial specialization. Epithelial cells at the bottom of crypts proliferate and migrate upwards toward the tips of the villi in the small intestine or the surface in the colon, where they die and slough off or are taken up by underlying phagocytic cells.

show abstract

Section: Discussionsupporting

confidence: 60%

mentioning

confidence: 99%

See 1 more Smart Citation

Coordinate Down-regulation of Adenylyl Cyclase Isoforms and the Stimulatory G Protein (Gs) in Intestinal Epithelial Cell Differentiation

Choi

Jeníková

Hanson

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These cells secrete chloride into the lumen in response to a broad spectrum of extracellular stimuli, including adenosine and cholera toxin, using calcium and cyclic nucleotides as intracellular mediators. [15][16][17][18] This chloride secretion establishes an osmotic gradient that draws sodium and water across the tight junction, resulting in net fluid secretion. [19][20][21][22] Under normal conditions, the undifferentiated crypt cells mature into mucin-secreting goblet cells and absorptive enterocytes that express nutrient and ion transporters as they proliferate and migrate to the villus tip (Fig.…”

Section: Small Intestinementioning

confidence: 99%

Good fences make good neighbors

Turner

2010

Gut Microbes

View full text Add to dashboard Cite

“…Inserts (0.4-m pore size; Costar, Cambridge, MA) were rested in wells that contained medium until steady-state resistance was achieved, as described (16,17). Caco2-BBe cells and HT29-Cl.19A cells were grown in Dulbecco's modified Eagle's medium, supplemented with 14 mmol/liter NaHCO 3 , 10% fetal bovine serum, and penicillin/streptomycin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Kolachala

Wang

Obertone

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

We have reported that epithelial adenosine 2B receptor (A 2B AR) mRNA and protein are up-regulated in colitis, which we demonstrated to be regulated by tumor necrosis factor ␣ (TNF-␣). Here, we examined the mechanism that governs A 2B AR expression during colitis. A 1.4-kb sequence of the A 2B AR promoter was cloned into the pFRL7 luciferase vector. Anti-microRNA (miRNA) was custom-synthesized based on specific miRNA binding sites. The binding of miRNA to the 3-untranslated region (UTR) of A 2B AR mRNA was examined by cloning this 3-UTR downstream of the luciferase gene in pMIR-REPORT. In T84 cells, TNF-␣ induced a 35-fold increase in A 2B AR mRNA but did not increase promoter activity in luciferase assays. By nuclear run-on assay, no increase in A 2B AR mRNA following TNF-␣ treatment was observed. Four putative miRNA target sites (miR27a, miR27b, miR128a, miR128b) in the 3-UTR of the A 2B AR mRNA were identified in T84 cells and mouse colon. Pretreatment of cells with TNF-␣ reduced the levels of miR27b and miR128a by 60%. Over expression of premiR27b and pre-miR128a reduced A 2B AR levels by >60%. Blockade of miR27b increased A 2B AR mRNA levels by 6-fold in vitro. miR27b levels declined significantly in colitis-affected tissue in mice in the presence of increased A 2B AR mRNA. Collectively, these data demonstrate that TNF-␣-induced A 2B AR expression in colonic epithelial cells is post-transcriptionally regulated by miR27b and miR128a and show that miR27b influences A 2B AR expression in murine colitis.

show abstract

Interferon-γ Down-regulates Adenosine 2b Receptor-mediated Signaling and Short Circuit Current in the Intestinal Epithelia by Inhibiting the Expression of Adenylate Cyclase

Abstract: Adenosine is an endogenous signaling molecule that is highly up-regulated in inflammatory states. Adenosine acts through the A2b receptor, a G protein-coupled receptor that couples positively to G␣ s and activates ad-

Cited by 34 publications

References 58 publications

Coordinate Down-regulation of Adenylyl Cyclase Isoforms and the Stimulatory G Protein (Gs) in Intestinal Epithelial Cell Differentiation

Coordinate Down-regulation of Adenylyl Cyclase Isoforms and the Stimulatory G Protein (Gs) in Intestinal Epithelial Cell Differentiation

Good fences make good neighbors

Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Contact Info

Product

Resources

About