Tumor necrosis factor (TNF) ? is a pleiotropic cytokine that induces cellular responses including proliferation, production of inflammatory mediators, and cell death and plays a major role in the pathophysiology of shock, inflammation, and the wasting syndrome. The initial period of this grant focused on the role of TNF? in inhibiting Type I collagen gene expression and the effect of TNF? on stimulating collagenase-1 gene expression with the net result of inhibiting fibrosis. However, we have subsequently discovered that TNF1 has a wide variety of effects on wound healing, including the induction of apoptosis in parenchymal cells, the induction of JNK with subsequent phosphorylation of Mcl-1 and other targets of apoptosis, the induction of reactive oxygen species, and the induction of the profribrogenic cytokine TGF?. Therefore, the current application will study hepatic fibrosis as a model of wound healing and address the following four specific aims: 1. To determine the role of the 5'Stem Loop of collagen ?1(I) mRNA in fibrosis. 2. To determine the role of TNF? and its receptor signaling in hepatic fibrosis. 3. To investigate how TNF1/TNFR-induced NFkB and JNK activation is coordinated by NOX derived ROS in HSC. 4. To assess the role of TNF1 induced JNK activation on hepatocyte apoptosis.

Public Health Relevance

Tumor necrosis factor (TNF)? is a multifunctional cytokine that is induced during inflammation and wound healing. TNF? has both anti-fibrotic effects on Type I collagen and pro-fibrotic effects on activating myofibroblasts. This proposal uses the wound healing model of hepatic fibrosis to assess how TNF? modulates wound healing through different signal transduction pathways in the whole organism and in specific hepatic cell populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041804-24
Application #
8016714
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1989-04-01
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
24
Fiscal Year
2011
Total Cost
$302,851
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Karin, Daniel; Koyama, Yukinori; Brenner, David et al. (2016) The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation 92:84-92
Lan, Tian; Kisseleva, Tatiana; Brenner, David A (2015) Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS One 10:e0129743
Kim, In Hee; Kisseleva, Tatiana; Brenner, David A (2015) Aging and liver disease. Curr Opin Gastroenterol 31:184-91
Brenner, David A; Paik, Yong-Han; Schnabl, Bernd (2015) Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol 49 Suppl 1:S25-7
Liu, Cheng; Chen, Xiaorong; Yang, Ling et al. (2014) Transcriptional repression of the transforming growth factor β (TGF-β) Pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 enhances TGF-β signaling in hepatic stellate cells. J Biol Chem 289:7082-91
Paik, Yong-Han; Kim, Jonghwa; Aoyama, Tomonori et al. (2014) Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal 20:2854-72
Iwaisako, Keiko; Jiang, Chunyan; Zhang, Mingjun et al. (2014) Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 111:E3297-305
Madsen, Daniel H; Leonard, Daniel; Masedunskas, Andrius et al. (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol 202:951-66
De Minicis, Samuele; Kisseleva, Tatiana; Francis, Heather et al. (2013) Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma. Dig Liver Dis 45:450-9
Schnabl, Bernd; Brenner, David A (2013) Fibroblast growth factor inducible 14 as potential target in patients with alcoholic hepatitis. Gut 62:335-6

Showing the most recent 10 out of 113 publications