DYSREGULATION OF CHOLANGIOCYTE APOPTOSIS BY CYTOKINES

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date9/30/988/31/04

ASJC

  • Medicine(all)