Chronic inflammation in gastrointestinal epithelia is characterized by alterations in the cytokine milieu and often predisposes to the development of neoplasia. Primary sclerosing cholangitis, a chronic inflammatory condition affecting the biliary system, is associated with cytokine alterations and the development of cholangiocarcinoma. Dysregulation of apoptosis has recently been implicated as an important contributor to carcinogenesis. We have recently shown that the pro- inflammatory cytokine IL-6 alters the susceptibility of biliary epithelial cells to undergo apoptosis by downregulating Bax, a member of the Bcl-2 family and a dominant tumor suppressor and pro-apoptotic gene. Thus, our HYPOTHESIS is that dysregulation of apoptosis by cytokines is an important mechanism of malignant transformation of biliary epithelia.
The SPECIFIC AIMS for this proposal are: 1) To test the hypothesis that pro-inflammatory cytokines such as IL-1, IL-6 and TNFalpha regulate apoptosis by altering the expression or activity of members of the Bcl-2 family of apoptosis regulators; 2) to test the hypothesis that IL-6 alters expression of Bax by a ligand mediated activation of specific signaling pathways resulting in altered gene transcription; and 3) to test the hypothesis that dysregulation of apoptosis by cytokines enhances malignant transformation in biliary epithelial cells due to genotoxic injury. These studies will help to determine the role of cytokines in injury and transformation of biliary epithelia and expand our understanding of the mechanisms mediating malignant transformation in inflammatory states. This information has the promise of ultimately contributing to the development of specific therapies for the cholangiopathies as well as interventions to prevent neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002678-02
Application #
2905020
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M,
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scott and White Memorial Hospital
Department
Type
DUNS #
076697960
City
Temple
State
TX
Country
United States
Zip Code
76504
Yamagiwa, Yoko; Marienfeld, Carla; Meng, Fanyin et al. (2004) Translational regulation of x-linked inhibitor of apoptosis protein by interleukin-6: a novel mechanism of tumor cell survival. Cancer Res 64:1293-8
Marienfeld, Carla; Tadlock, Laura; Yamagiwa, Yoko et al. (2003) Inhibition of cholangiocarcinoma growth by tannic acid. Hepatology 37:1097-104
Patel, Tushar (2003) Aberrant local renin-angiotensin II responses in the pathogenesis of primary sclerosing cholangitis. Med Hypotheses 61:64-7
Yamagiwa, Yoko; Marienfeld, Carla; Tadlock, Laura et al. (2003) Translational regulation by p38 mitogen-activated protein kinase signaling during human cholangiocarcinoma growth. Hepatology 38:158-66
Alpini, Gianfranco; Ueno, Yoshiyuki; Tadlock, Laura et al. (2003) Increased susceptibility of cholangiocytes to tumor necrosis factor-alpha cytotoxicity after bile duct ligation. Am J Physiol Cell Physiol 285:C183-94
Tadlock, Laura; Yamagiwa, Yoko; Hawker, James et al. (2003) Transforming growth factor-beta inhibition of proteasomal activity: a potential mechanism of growth arrest. Am J Physiol Cell Physiol 285:C277-85
Patel, Tushar (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10
Sheth, Milan; Riggs, Mark; Patel, Tushar (2002) Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. BMC Gastroenterol 2:2
Patel, T (2001) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33:1353-7
Tadlock, L; Patel, T (2001) Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line. Hepatology 33:43-51

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