Dataset Information

The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae.

ABSTRACT:

Background

One of the most challenging conditions in Crohn's disease (CD) patients is the treatment of perianal fistulae. We have recently shown that epithelial-to-mesenchymal transition (EMT) plays a crucial role during CD-fistulae development. Dickkopf-homolog 1 (DKK-1) is known to play a key role during EMT. Here, we investigated a role for DKK-1 in the pathogenesis of CD-associated fistulae.

Methods

Dkk-1 protein expression in CD-fistula specimens were investigated by immunohistochemistry. Colonic lamina propria fibroblasts (CLPF) were obtained from either non-IBD control patients or patients with fistulizing CD. HT-29 intestinal epithelial cells (IEC) were either grown as monolayers or spheroids. Cells were treated with either TNF-?, TGF-? or IL-13. Knock-down of DKK-1 or ?-Catenin was induced in HT-29-IEC by siRNA technique. mRNA expression was determined by real-time-PCR.

Results

Dkk-1 protein was specifically expressed in transitional cells lining the fistula tracts. TGF-? induced DKK-1 mRNA expression in HT-29-IEC, but decreased it in fistula CLPF. On a functional level, DKK-1 knock-down prevented TGF-?-induced IL-13 mRNA expression in HT-29-IEC. Further, loss of ?-Catenin was accompanied by reduced levels of DKK-1 and, again, IL-13 in IEC in response to TGF-?. In turn, treatment of HT-29-IEC as well as fistula CLPF with IL-13 resulted in decreased levels of DKK-1 mRNA. Treatment with TNF-? or the bacterial wall component, muramyl-dipeptide, decreased DKK-1 mRNA levels in HT-29-IEC, but enhanced it in fistula CLPF.

Discussion

We demonstrate that DKK-1 is strongly expressed in cells lining the CD-fistula tracts and regulates factors involved in EMT initiation. These data provide evidence for a role of DKK-1 in the pathogenesis of CD-associated perianal fistulae.

SUBMITTER: Frei SM

PROVIDER: S-EPMC3826763 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae.

Frei Sandra Michaela SM Hemsley Colette C Pesch Theresa T Lang Silvia S Weber Achim A Jehle Ekkehard E Rühl Anne A Fried Michael M Rogler Gerhard G Scharl Michael M

PloS one 20131108 11

<h4>Background</h4>One of the most challenging conditions in Crohn's disease (CD) patients is the treatment of perianal fistulae. We have recently shown that epithelial-to-mesenchymal transition (EMT) plays a crucial role during CD-fistulae development. Dickkopf-homolog 1 (DKK-1) is known to play a key role during EMT. Here, we investigated a role for DKK-1 in the pathogenesis of CD-associated fistulae.<h4>Methods</h4>Dkk-1 protein expression in CD-fistula specimens were investigated by immunohi ...[more]

PMID: 24250816

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Project description:Testicular Sertoli cells (Sc) are main somatic component of seminiferous tubules that govern the differentiation of germ cells (Gc) and provide them physical support. Sc are the target of follicle stimulating hormone (FSH) and testosterone (T) which are known to regulate spermatogenesis. FSH and T levels in human and sub-human male primates remain high during infancy (4-6 months post birth), similar to those during puberty. Subsequently, juvenile phase is marked with low levels of these hormones. In spite of prolonged hormonal exposure, spermatogenesis is not discerned during infancy unlike that during puberty. Situation during infancy is similar to certain idiopathic male infertility, where prolonged hormone supplementation fails to initiate spermatogenesis. In our quest to determine non hormonal causes of idiopathic infertility which may reside within the Sc, we investigated the association between spermatogenesis and Sc specific gene(s) expressed differentially during puberty and infancy. Although products of several genes may be necessary for quantitatively normal spermatogenesis, one needs to investigate their roles one by one. Differential display and real time PCR analysis revealed higher expression of a known tumor suppressor, Dickkopf homolog 3 (DKK3), by pubertal monkey Sc as compared to infant Sc. To evaluate role of DKK3 in spermatogenesis, we generated DKK3 knock down mice (DKDM) using shRNA construct targeted to DKK3. In testis of adult DKDM, expression of DKK3 mRNA and protein were significantly (p<0.05) low and was associated with elevated WNT-4/?-CATENIN activity. Elevated ?-CATENIN activity is known to restrict Sc maturation. Abundant expression of infant Sc marker, Mullerian inhibiting substance (MIS), in the testes of adult DKDM confirmed lack of Sc maturation in DKDM. Gc differentiation and fertility was severely compromised in DKDM. This is the first report of role of DKK3 in the testis and DKK3 mediated regulation of spermatogenesis via WNT-4/?-CATENIN modulation.

Dataset Information

The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae.

Background

Methods

Results

Discussion

Publications

The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae.

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