Prause Michala, Berchtold Lukas Adrian, Urizar Adriana Ibarra, Hyldgaard Trauelsen Mette, Billestrup Nils, Mandrup-Poulsen Thomas, Størling Joachim
Immunoendocrinology Laboratory, Endocrinology Research Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Mol Cell Endocrinol. 2016 Jan 15;420:24-36. doi: 10.1016/j.mce.2015.11.021. Epub 2015 Nov 22.
Interleukin-1β (IL-1β) and interferon-γ (IFNγ) contribute to type 1 diabetes (T1D) by inducing β-cell death. Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins are adaptors that transduce signaling from a variety of membrane receptors including cytokine receptors. We show here that IL-1β and IFNγ upregulate the expression of TRAF2 in insulin-producing INS-1E cells and isolated rat pancreatic islets. siRNA-mediated knockdown (KD) of TRAF2 in INS-1E cells reduced IL-1β-induced phosphorylation of JNK1/2, but not of p38 or ERK1/2 mitogen-activated protein kinases. TRAF2 KD did not modulate NFκB activation by cytokines, but reduced cytokine-induced inducible nitric oxide synthase (iNOS) promotor activity and expression. We further observed that IFNγ-stimulated phosphorylation of STAT3 required TRAF2. KD of TRAF2 or STAT3 reduced cytokine-induced caspase 3/7 activation, but, intriguingly, potentiated cytokine-mediated loss of plasma membrane integrity and augmented the number of propidium iodide-positive cells. Finally, we found that TRAF2 KD increased cytokine-induced production of reactive oxygen species (ROS). In summary, our data suggest that TRAF2 is an important mediator of IL-1β and IFNγ signaling in pancreatic β-cells.
白细胞介素-1β（IL-1β）和干扰素-γ（IFNγ）通过诱导β细胞死亡而导致1型糖尿病（T1D）。肿瘤坏死因子（TNF）受体相关因子（TRAF）蛋白是衔接蛋白，可转导来自包括细胞因子受体在内的多种膜受体的信号。我们在此表明，IL-1β和IFNγ可上调胰岛素生成的INS-1E细胞和分离的大鼠胰岛中TRAF2的表达。在INS-1E细胞中，小干扰RNA（siRNA）介导的TRAF2敲低（KD）可降低IL-1β诱导的JNK1/2磷酸化，但不影响p38或ERK1/2丝裂原活化蛋白激酶的磷酸化。TRAF2 KD并未调节细胞因子对NFκB的激活，但降低了细胞因子诱导的诱导型一氧化氮合酶（iNOS）启动子活性和表达。我们进一步观察到，IFNγ刺激的STAT3磷酸化需要TRAF2。TRAF2或STAT3的KD可降低细胞因子诱导的半胱天冬酶3/7激活，但有趣的是，增强了细胞因子介导的质膜完整性丧失，并增加了碘化丙啶阳性细胞的数量。最后，我们发现TRAF2 KD增加了细胞因子诱导的活性氧（ROS）生成。总之，我们的数据表明，TRAF2是胰腺β细胞中IL-1β和IFNγ信号传导的重要介质。
