A critical role for CK2 in cytokine-induced activation of NF kappa B in pancreatic beta cell death

作者：Jaksch Caroline; Thams Peter^*

来源：Endocrine, 2014, 47(1): 117-128.

DOI：10.1007/s12020-013-0133-6

• beta cell
• Islet
• CK2
• Cytokine
• NF kappa B
• STAT1

This study aimed to assess the role of constitutive protein kinase CK2 in cytokine-induced activation of NF kappa B in pancreatic beta cell death. The CK2 inhibitors DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) (50 mu M) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) (5 mu M), which decreased CK2 activity by approx. 65 %, rescued INS-1E beta cells and mouse islets from cytokine (IL-1 beta, TNF-alpha plus IFN-gamma)-induced beta cell death without affecting H2O2- or palmitate-induced beta cell death. Western blot analysis revealed that while DRB or DMAT did not influence cytokine-induced I kappa B alpha degradation, they inhibited NF kappa B-dependent I kappa B alpha resynthesis, demonstrating that cytokine-induced NF kappa B activity is dependent on CK2. Both DRB and DMAT inhibited the constitutive phosphorylation of NF kappa B p65 at serine 529, while leaving cytokine-induced phosphorylations of NF kappa B p65 at serines 276 and 536 unaltered. In comparison, putative phosphorylation sites for CK2 on HDACs 1, 2, and 3 at serines 421/423, 394, and 424, respectively, which may stimulate NF kappa B transcriptional activity, were unchanged by cytokines and CK2 inhibitors. Whereas IL-1 beta and TNF-alpha stimulate I kappa B alpha degradation and NF kappa B activation, IFN-gamma potentiates cytokine-induced beta cell death through activation of STAT1. DRB and DMAT inhibited IFN-gamma-stimulated phosphorylation of STAT1 at serine 727, while leaving IFN-gamma-induced phosphorylation of STAT1 at tyrosine 701 unaffected. Inhibition of cytokine-induced beta cell death by CK2 inhibitors was, however, not dependent on IFN-gamma, and IFN-gamma did not affect CK2-dependent I kappa B alpha turnover. In conclusion, it is suggested that cytokine-induced activation of NF kappa B in beta cells is dependent on CK2 activity, which phosphorylates NF kappa B p65 at serine 529.

• 出版日期2014-9