Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis

Tin K. Mao, Yasunori Kimura, Thomas P. Kenny, Andrea Branch, Robert G. Gish, Judy Van De Water, Hsing Jien Kung, Scott L. Friedman, M. Eric Gershwin

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Primary biliary cirrhosis (PBC) is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and cholestasis, leading to fibrosis. Methods: We utilized a novel restriction analysis system to profile the expression of tyrosine kinases (TKs). This methodology targets a conserved sequence present in the majority of human TKs, and exploits the known restriction map of the TK cDNA sequences. We isolated mRNA from biliary epithelial cell (BEC)-enriched cell fractions, amplified the TK transcripts using degenerative primers, and identified specific TKs by restriction enzyme digest analysis and then performed in situ hybridization. Results: BEC-enriched samples from PBC livers displayed marked expression of discoidin domain receptor-2 (DDR2), whereas, non-diseased livers showed no detectable DDR2. Furthermore, in situ hybridization of PBC livers revealed that DDR2 is expressed in the small bile duct epithelial regions as well as in fibroblasts/stromal cells of fibrotic regions. A similar pattern was observed in livers of primary sclerosing cholangitis (PSC), although the amount of small ducts that were positively stained was lower than in PBC. Furthermore, cirrhotic livers of patients with other diseases, including alcoholic liver disease and chronic hepatitis C, DDR2 transcripts were noted only within fibrotic lesions and the degree of intensity was much lower than in PBC and PSC. Conclusions: DDR2, a TK that is stimulated by fibrillar collagens that accumulate in cirrhotic livers, is present at elevated levels in the small bile ducts of PBC patients. DDR2 is part of a positive feedback loop in which its enhanced expression leads to enhanced deposition of fibrillar collagens (types I and III). These fibrillar collagens can also provide binding sites for immune mediators, such as cytokines and chemokines. Therefore, unusually high DDR2 expression in the bile ducts of PBC patients could contribute to duct injury by altering local cytokine levels and thereby increasing immune-mediated damage.

Original languageEnglish
Pages (from-to)521-529
Number of pages9
JournalAutoimmunity
Volume35
Issue number8
DOIs
Publication statusPublished - Dec 1 2002
Externally publishedYes

Fingerprint

Biliary Liver Cirrhosis
Protein-Tyrosine Kinases
Fibrillar Collagens
Liver
Bile Ducts
Sclerosing Cholangitis
In Situ Hybridization
Epithelial Cells
Cytokines
Intrahepatic Bile Ducts
Alcoholic Liver Diseases
Restriction Mapping
Collagen Type III
Conserved Sequence
Cholestasis
Chronic Hepatitis C
Stromal Cells
Collagen Type I
Discoidin Domain Receptor 2
Chemokines

Keywords

  • Fibrosis
  • Primary biliary cirrhosis
  • Tyrosine kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mao, T. K., Kimura, Y., Kenny, T. P., Branch, A., Gish, R. G., Van De Water, J., ... Gershwin, M. E. (2002). Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Autoimmunity, 35(8), 521-529. https://doi.org/10.1080/0891693021000057784

Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. / Mao, Tin K.; Kimura, Yasunori; Kenny, Thomas P.; Branch, Andrea; Gish, Robert G.; Van De Water, Judy; Kung, Hsing Jien; Friedman, Scott L.; Gershwin, M. Eric.

In: Autoimmunity, Vol. 35, No. 8, 01.12.2002, p. 521-529.

Research output: Contribution to journalArticle

Mao, TK, Kimura, Y, Kenny, TP, Branch, A, Gish, RG, Van De Water, J, Kung, HJ, Friedman, SL & Gershwin, ME 2002, 'Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis', Autoimmunity, vol. 35, no. 8, pp. 521-529. https://doi.org/10.1080/0891693021000057784
Mao TK, Kimura Y, Kenny TP, Branch A, Gish RG, Van De Water J et al. Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Autoimmunity. 2002 Dec 1;35(8):521-529. https://doi.org/10.1080/0891693021000057784
Mao, Tin K. ; Kimura, Yasunori ; Kenny, Thomas P. ; Branch, Andrea ; Gish, Robert G. ; Van De Water, Judy ; Kung, Hsing Jien ; Friedman, Scott L. ; Gershwin, M. Eric. / Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. In: Autoimmunity. 2002 ; Vol. 35, No. 8. pp. 521-529.
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AB - Background: Primary biliary cirrhosis (PBC) is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and cholestasis, leading to fibrosis. Methods: We utilized a novel restriction analysis system to profile the expression of tyrosine kinases (TKs). This methodology targets a conserved sequence present in the majority of human TKs, and exploits the known restriction map of the TK cDNA sequences. We isolated mRNA from biliary epithelial cell (BEC)-enriched cell fractions, amplified the TK transcripts using degenerative primers, and identified specific TKs by restriction enzyme digest analysis and then performed in situ hybridization. Results: BEC-enriched samples from PBC livers displayed marked expression of discoidin domain receptor-2 (DDR2), whereas, non-diseased livers showed no detectable DDR2. Furthermore, in situ hybridization of PBC livers revealed that DDR2 is expressed in the small bile duct epithelial regions as well as in fibroblasts/stromal cells of fibrotic regions. A similar pattern was observed in livers of primary sclerosing cholangitis (PSC), although the amount of small ducts that were positively stained was lower than in PBC. Furthermore, cirrhotic livers of patients with other diseases, including alcoholic liver disease and chronic hepatitis C, DDR2 transcripts were noted only within fibrotic lesions and the degree of intensity was much lower than in PBC and PSC. Conclusions: DDR2, a TK that is stimulated by fibrillar collagens that accumulate in cirrhotic livers, is present at elevated levels in the small bile ducts of PBC patients. DDR2 is part of a positive feedback loop in which its enhanced expression leads to enhanced deposition of fibrillar collagens (types I and III). These fibrillar collagens can also provide binding sites for immune mediators, such as cytokines and chemokines. Therefore, unusually high DDR2 expression in the bile ducts of PBC patients could contribute to duct injury by altering local cytokine levels and thereby increasing immune-mediated damage.

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