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Slug-dependent UVR induction of cytokines and chemokines

ABSTRACT: Studies of the zinc finger transcription factors Slug and Snail have largely focused on their important role in modulating epithelial-mesenchymal transition during embryonic development and tumor progression. However, these transcription factors also appear to regulate local inflammation. In previous studies, we showed that Slug knockout mice were resistant to sunburn, an acute cutaneous inflammatory response, compared to wild type mice. In the present studies, we used Slug knockout, chimeric Slug knockout/wild type, conditional Slug knockout, and Slug transgenic mice to study the role of Slug in ultraviolet radiation (UVR)-induced cutaneous inflammation. We demonstrated, using immunohistochemistry, in vivo imaging, and neutrophil migration studies, that it was Slug expression in the epidermis rather than in neutrophils that modulated the UVR response. Microarray analysis indicated that this modulation was effected by the production of epidermal cytokines, including CCL3, CCL4, oncostatin, and interleukin-1β, that recruited neutrophils to UVR-exposed skin. The pattern of pro-inflammatory gene regulation by Slug suggested a central role for NF-κB in mediating gene induction. Immunohistochemical analysis of UVR-induced NF-κB activation demonstrated reduced activation in Slug knockout and enhanced activation in Slug transgenic epidermis. Slug thus appears to modulate NF-κB activation in response to UVR.

ORGANISM(S): Mus musculus

PROVIDER: GSE86107 | GEO | 2016/08/27

SECONDARY ACCESSION(S): PRJNA340275

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Slug-dependent UVR induction of cytokines and chemokines

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