IB1 Reduces Cytokine-induced Apoptosis of Insulin-secreting Cells

Abstract

IB1/JIP-1 are recently characterized mammalian scaffold proteins involved in the regulation of the JNK 1 signaling pathway (1-3). These two isoforms bind to and associate in a single transduction complex three kinases, MLK3, MKK7, and JNK, which together constitute an ordered unit of sequential signaling molecules transducing a variety of stress signals (2, 3). To date, five different isoforms of the protein have been cloned, which are mainly N-terminal splice variants that arise from expression of one single gene on human chromosome 11p11.2-p12 (1, 4, 5). A S59N mutation close to the JNK binding domain of IB1 has recently been associated with a late onset type 2 diabetes (6). Functionally, this mutation led to an increased susceptibility of JNK-mediated apoptosis in different cell systems, implying a presumably important functional role of IB1 in controlling the cell response to proapoptotic stimuli (6).Interleukin 1 (IL-1␤), which activates JNK essentially through the MKK7 pathway in several cells and tissues (7-10), is believed to play a key role in the process of selective ␤ cell destruction observed in type 1 diabetes. Chronic exposure of pancreatic islets or of ␤-derived cell lines to IL-1␤ had been shown to lead to the selective death of the ␤ cells, whereas non-␤ cells such as glucagon-producing cells appeared more resistant to the action of the cytokine (reviewed in Refs. 11-15). The molecular basis for the preferential killing of pancreatic ␤ versus ␣ cells by IL-1␤ is not fully understood. One important player in this phenomenon is the inducible nitric-oxide synthase gene iNOS, which is specifically expressed in the ␤ cells upon IL-1␤ treatment (16 -20). A number of reports have indeed clearly shown that ␤ cell apoptosis is NO-dependent (see for example two recent reports (21, 22)). In line with this, pancreatic islets from iNOS KO mice show a better resistance to IL-1␤ cytotoxicity (23).This NO-dependent killing of ␤ cells has been, however, challenged by several reports pointing to the existence of NOindependent death signaling pathways (24, 25). For example, there is no direct correlation between expression of iNOS and sensitivity to IL-1␤ between ␤ cells at different stages of differentiation (26). Importantly, the iNOS inhibitor L-NMMA does not prevent IL-1␤-induced ␤ cell death in rat or human islets (24,25). It is also possible to block NO synthesis by blocking the extracellular signal-regulated kinase and p38 MAP kinase pathways, however, without any positive effect on cell survival (17).To better understand the molecular mechanisms that specifically sensitize ␤ cells to IL-1␤-induced death, we recently used two different subclones of the pluripotent pancreatic endocrine stem cell clone (MSL). The MSL AN697C1 subclone gave rise to two derived cell lines, namely the glucagon-secreting AN-glu, and after stable transfection with the transcription factor pancreatic duodenal homeobox factor-1, the insulin secreting ANins (27). Despite having similar rates of NO synthesis, we found that the AN-ins c...

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

“…26 It has been also reported that JNK activation is increased following transient global focal ischaemia, in particular in the CA1 neurons of the hippocampus. 27 In other cell systems, IB1/JIP-1 was shown to be downregulated once cells were exposed to various stresses such as UV, cytokines, parietal stress or starving 10,28 . As a consequence, JNK activity is increased and the cells undergo a pro-apoptotic pathway.…”

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

“…It is known that beta cell destruction by cytokines such as IL-1β [34,35] can be prevented by inhibition of the JNK pathway [24,36], implying that JNK plays a role in the autoimmune beta cell destruction found in the early stage of type 1 diabetes. In addition, the JNK pathway is activated in various tissues, including pancreatic islets, in the diabetic state, and suppression of that pathway reduces insulin resistance and ameliorates glucose intolerance in type 2 diabetic animal models [37].…”

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome

“…57,58 MAPK8IP1 Mitogen-activated protein kinase 8 interacting protein 1 MAPK8IP1 is a regulator of pancreatic beta-cell function and has been shown to prevent MAPK8-mediated activation of transcription factors, and decrease IL-1 beta and MAP kinase 1 (MEKK1)-induced apoptosis in pancreatic beta cells. 59 MAPK8IP1 has also been shown to be a DNA-binding transactivator of the glucose transporter GLUT2, and mutations in MAPK8IP1 have been shown to be associated with type 2 diabetes. 60 MAPK8IP1À/À mice die before blastocyst implantation suggesting that it is required for early embryogenesis in mice.…”