Tissue Inhibitor of Metalloproteinase-1 Prevents Cytokine-Mediated Dysfunction and Cytotoxicity in Pancreatic Islets and β-cells

Abstract

MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) are tightly regulated enzymes that coordinate matrix production and degradation. The obvious need for a dynamic process that regulates collagen turnover is evident in wound repair and remodeling (2,3). However, MMPs and TIMPs are involved in other significant but less obvious processes, such as tumor invasion and metastasis (4 -7), inflammatory responses (8), embryonic development (9,10), arthritic diseases (11,12), and multiple sclerosis (13,14).Recently, Herren et al. (15) discovered that certain metalloproteinases play a role in apoptosis. In particular, MMPs play a role in caspase activation by processing membrane-bound ␤-catenin to its active form via proteolysis. MMPs may also be involved in processing the transmembrane Fas ligand to the soluble Fas ligand (16). In addition, MMPs convert the membrane-bound form of protumor necrosis factor (TNF)-␣ to the mature active inflammatory cytokine through proteolytic cleavage of a critical alanine-valine bond at amino acids 76 and 77 (17,18).Alternatively, TIMP-1 overexpression prevented programmed cell death in a Burkitt's lymphoma cell line through both CD-95 (Fas)-dependent and -independent pathways. TIMP-1 overexpression upregulated Bcl-xL and decreased nuclear factor (NF)-B activity, and the protective effect was not related to metalloproteinase inhibition (19). Furthermore, TIMP-1 expression has been used to prevent apoptotic cell death induced by hydrogen peroxide, adriamycin, and X-ray irradiation in human breast epithelial cell lines (20).Pancreatic ␤-cells and islets are particularly sensitive to cytokine-mediated damage. Cytokine-treated rodent (and human) pancreatic islets demonstrate increased expression of the inducible nitric oxide synthase (iNOS) gene that in turn leads to nitric oxide (NO) production (21). NO inhibits glucose-stimulated insulin secretion (GSIS) and induces ␤-cell damage. Whereas inhibitors of iNOS, such as N-monomethyl-L arginine and L-N-arginine-methylester, can partially prevent cytokine-mediated ␤-cell damage through inhibition of NO production; NO-independent From the Leslie and Susan Gonda

NF-κB prevents β cell death and autoimmune diabetes in NOD mice

“…The underlying cause for this discrepancy is not entirely clear but could be due to differences in culture condition or cytokine treatment (12)(13)(14)(15). Indeed, most studies that found a proapoptotic function for NF-B used IL-1 or chemical toxins rather than TNF-␣ plus IFN-␥ to elicit islet cell death (17,18,20,21,44). We also confirmed a proapoptotic function for NF-B by using a combination of IL-1␤ plus IFN-␥.…”

Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest

“…Male ICR mice (20-25 g; purchased from Shanghai Laboratory Animal Centre, Chinese Academy of Sciences, Shanghai, People's Republic of China) were used. Islet isolation and culturing techniques have been described previously [21]. Freshly isolated islets were transferred to sterile six well plates and cultured in DMEM containing 11.1 mmol/l glucose supplemented with 10% FBS.…”

Identification of direct forkhead box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation

“…A mouse model of type 2 diabetes (db/db mice; BKS.Cg-m +/+ Leprdb/J) was used (Model Animal Research Center of Nanjing University, Nanjing, China). Islet isolation and culturing techniques have been described previously [25].…”

“…To do this, a transfection kit reagent (NanoJuice; Merck, Darmstadt, Germany) was used according to the manufacturer's instructions. At 24 h after transfection, cells were collected for the luciferase assay as described previously [25].…”