Systemic delivery of TNF-related apoptosis-inducing ligand (TRAIL) elevates levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and prevents type 1 diabetes in nonobese diabetic mice.
Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.
Department of Pharmacology, Dong-A University College of Medicine, Busan, South Korea.
Soojeong
S
Kang
Eun-Jin
EJ
Park
Yeonsoo
Y
Joe
Eunhui
E
Seo
Mi-Kyoung
MK
Park
Su-Young
SY
Seo
Hae-Young
HY
Chung
Young Hyun
YH
Yoo
Duk Kyu
DK
Kim
Hye-Jeong
HJ
Lee
D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1