Bilirubin promotes de novo generation of T regulatory cells.

We have previously demonstrated that bilirubin administration to the recipient induces tolerance towards islet cell transplants across a complete MHC mismatch in a mouse model. Here we assess the mechanisms of such protection. Bilirubin treatment of recipients improved function of islet allografts by suppressing expressions of proinflammatory and proapoptotic genes in those islets and by increasing Foxp3(+) T regulatory (Treg) cells at the site of transplanted islets at various days after transplantation.

Toll-like receptor 4 suppression leads to islet allograft survival.

Carbon monoxide (CO) exposure of an islet donor frequently leads to islet allograft long-term survival and tolerance in recipients. We show here that CO confers its protective effects at least in part by suppressing Toll-like receptor 4 (TLR4) up-regulation in pancreatic beta cells. TLR4 is normally up-regulated in islets during the isolation procedure; donor treatment with CO suppresses TLR4 expression in isolated islets as well as in transplanted grafts.

A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia.

A20 is a NF-kappaB-dependent gene that has dual anti-inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti-inflammatory function via blockade of NF-kappaB and NF-kappaB-dependent proteins ICAM-1 and MCP-1.

Bilirubin can induce tolerance to islet allografts.

Induction of heme oxygenase-1 (HO-1) expression in recipients of allogeneic islets can lead to long-term survival (>100 d) of those islets. We tested whether administration of bilirubin would substitute for the beneficial effects of HO-1 expression in islet transplantation. Administering bilirubin to the recipient (B6AF1) or incubating islets in a bilirubin-containing solution ex vivo led to long-term survival of allogeneic islets in a significant percentage of cases.

Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells.

Background: Apoptotic death of renal proximal tubular epithelial cells (RPTECs) is a feature of acute and chronic renal failure. RPTECs are directly damaged by ischemia, inflammatory, and cytotoxic mediators but also contribute to their own demise by up-regulating proinflammatory nuclear factor-kappaB (NF-kappaB)-dependent proteins. In endothelial cells, the Bcl family member A1 and the zinc finger protein A20 have redundant and dual antiapoptotic and anti-inflammatory effects.