Exp Mol Med.  2010 Nov;42(11):739-748. 10.3858/emm.2010.42.11.075.

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

• Zhu H
• Wang J
• Jiang H
• Ma Y
• Pan S
• Reddy S
• Sun X

• KMID: 994397
• DOI: http://doi.org/10.3858/emm.2010.42.11.075

Abstract

Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1beta, TNF-alpha and IFN-gamma) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1beta, TNF-alpha, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.

Keyword

bilirubin; diabetes mellitus, type 1; inflammation; insulin-secreting cells; islet transplantation

MeSH Terms

Animals
Apoptosis/drug effects/immunology
Bilirubin/*administration & dosage/pharmacology
Cell Line, Tumor
Cytokines/immunology/metabolism
Diabetes Mellitus, Experimental/*drug therapy/*immunology
Inflammation
Inflammation Mediators/immunology/metabolism
Islets of Langerhans/drug effects/*immunology/injuries/pathology
*Islets of Langerhans Transplantation
Male
Oxidative Stress/drug effects/immunology
Rats
Rats, Inbred Lew
Transplantation, I