Dataset Information

Islet ?-cell Inflammation Induced By NF-?B inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

ABSTRACT: Islet ?-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet ?-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-?B inducing kinase (NIK) regulates pancreatic ?-cell function, both in vitro and in vivo, and to assess how islet ?-cell inflammation induced by NIK affects the development of pancreatitis. Methods: We utilized adenovirus-mediated NIK overexpression, ELISA, qPCR, RNA-seq, and Western blot analyses to study the role of NIK in islet ? cells in vitro. Islet ?-cell-specific NIK overexpressing (?-NIK-OE) mice were generated, and pancreatic ?/?-cell function and the occurrence of pancreatitis in these mice were assessed via ELISA, qPCR, and immunohistochemical analyses. Results: The LT?R/noncanonical NF-?B signaling pathway is present in islet ? cells. Overexpression of NIK in ?TC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, ?-cell specific overexpression of NIK (?-NIK-OE) results in ?-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, ?-NIK-OE mice also display a reduced ?-cell mass, growth retardation, pancreatitis, and postnatal death. Conclusions: Islet ?-cell specific overexpression of NIK results in islet ?-cell dysfunction and causes islet ?-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet ? cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice.

SUBMITTER: Li X

PROVIDER: S-EPMC6299425 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

Li Xinzhi X Jia Linna L Chen Xiaoyue X Dong Ying Y Ren Xiaomeng X Dong Yuefan Y Chen Ying Y Xie Liwei L Liu Ming M Shiota Chiyo C Gittes George K GK Rui Liangyou L Chen Zheng Z

Theranostics 20181113 21

Islet α-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet α-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-κB inducing kinase (NIK) regulates pancreatic α-cell function, both in vitro and in vivo, and to assess how islet α-cell inflammation induced by NIK affects the development of pancreatitis. Methods: We utilized adenovirus-mediated NIK overexpress ...[more]

PMID: 30613274

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Project description:Studies from global loss-of-function mutants suggest that alternative NF-κB downstream of NF-κB inducing kinase (NIK) is a cell-intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx-Cre;NT3 animals (NT3-Cre +), which bear a constitutively active NIK allele (NT3) driven by Osx-Cre, were compared with their Cre-negative, Control (Ctrl) littermates. NT3-Cre + mice had elevated serum P1NP and CTX levels. Despite this high turnover state, µCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3-Cre + mice exhibited a greater anabolic response following mechanical loading compared with controls. We next performed RNA-Seq on nonloaded and loaded tibias to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3-Cre + mice. Hierarchical clustering revealed two main transcriptional programs: one loading-responsive and the other NT3 transgene-driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase, and growth factor activities including Wnts, as well as a calcium-response signature in NT3-Cre + limbs. The promoters of these GO-term associated genes, including many known to be bone-anabolic, were highly enriched for multiple κB recognition elements (κB-RE) relative to the background frequency in the genome. The loading response in NT3-Cre + mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10-fold more DEGs in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple κB-RE in their promoters. Therefore, both transcriptional programs (loading-responsive and NT3 transgene-driven) are modulated by NF-κB. Our studies uncover a previously unrecognized role for NF-κB in the promotion of both basal and mechanically stimulated bone formation. © 2019 American Society for Bone and Mineral Research.

Dataset Information

Islet ?-cell Inflammation Induced By NF-?B inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

Publications

Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

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