Talk abstracts

Talk on Saturday 10:50-11:05am submitted by Erik Zmuda

Potential roles of ATF3 in pancreatic islet transplantation

Erik Zmuda (Molecular and Cellular Biochemistry, Ohio State University), Adolfo Garcia-Ocana (Division of Endocrinology, University of Pittsburgh), Tsonwin Hai (Molecular and Cellular Biochemistry, Ohio State University)

Abstract:
β-cell transplantation has emerged as a viable therapy for treating diabetes. Recent research focused on improving the yield of functional β-cells from donor pancreata has improved the therapeutic potential of this treatment. This research has highlighted the role β-cell apoptosis plays during transplantation(1-3). Given the known pro-apoptotic role of ATF3(4), we tested the hypothesis that ATF3 contributes to reduced yield of functional β-cells during transplantation.

Here we present data suggesting that ATF3 reduces the yield of β-cells from donor pancreata, at least in part, by modulating factors that influence β-cell function, apoptosis, and inflammation. In a mouse model of β-cell transplantation, diabetic recipients of β-cells from ATF3 knockout donors maintained glucose homeostasis better than mice receiving wild type β-cells. Analysis of β-cell response to transplantation relevant stresses revealed a mechanism by which ATF3 reduces the functional yield of donor β-cells. ATF3 promoted the expression of IL-1β, a cytokine known to impair insulin secretion. ATF3 contributed to the expression of pro-apoptotic genes Noxa and bNIP3. Lastly, ATF3 contributed to β-cell induction of tissue factor, a protein known to recruit pro-inflammatory immune cells.

In conclusion, our data suggests three previously unidentified functions of ATF3 that have the potential to influence the efficacy of β-cell transplantation by;
-promoting IL-1β expression, potentially reducing the function of β-cells.
-contributing to the expression of pro-apoptotic genes Noxa and bNIP3.
-increasing the expression of tissue factor, which may promote inflammation.

References:
1. Contreras et al., Cytoprotection of Pancreatic Islets Before and Soon After Transplantation by Gene Transfer of the Anti-apoptotic Bcl-2 Gene. Transplantation, April 2001, v.71, No. 8, p.1015-1023.
2. Nakano et al., Caspase-3 Inhibitor Prevents Apoptosis of Human Islets Immediately After Isolation and Improves Islet Graft Function. Pancreas, August 2004, v.29, No. 2, p. 104-109.
3. Plesner et al., The X-linked Inhibitor of Apoptosis Protein Enhances Survival of Murine Islet Allografts. Diabetes, September 2005, v. 54, p. 2533-2540.
4. Hartman et al., Role for Activating Transcription Factor 3 in Stress-Induced ß-Cell Apoptosis. Molecular and Cellular Biology, July 2004, Vol. 24, No. 13, p. 5721-5732.

Keywords: Diabetes, Inflammation, Transplantation