Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Aomori, Japan.
Cells. 2022 Apr 25;11(9):1451. doi: 10.3390/cells11091451.
Interleukin (IL)-3 is a pleiotropic cytokine that regulates the survival, proliferation, and differentiation of hematopoietic cells. The binding of IL-3 to its receptor activates intracellular signaling, inducing transcription of immediate early genes (IEGs) such as c-, c-, and c-; however, transcriptional regulation under IL-3 signaling is not fully understood. This study assessed the role of the inhibitor of nuclear factor-κB kinases (IKKs) in inducing IL-3-mediated expression of IEGs. We show that IKK1 and IKK2 are required for the IL-3-induced immediate expression of c- and c- in murine hematopoietic Ba/F3 cells. Although IKK2 is well-known for its pivotal role as a regulator of the canonical nuclear factor-κB (NF-κB) pathway, activation of IKKs did not induce the nuclear translocation of the NF-κB transcription factor. We further revealed the important role of IKK2 in the activation of c-Jun N-terminal kinase (JNK), which mediates the IL-3-induced expression of c- and c-. These findings indicate that the IKK2-JNK axis modulates the IL-3-induced expression of IEGs in a canonical NF-κB-independent manner.
白细胞介素 (IL)-3 是一种多效细胞因子，可调节造血细胞的存活、增殖和分化。IL-3 与其受体结合可激活细胞内信号转导，诱导即刻早期基因 (IEGs) 的转录，如 c-、c- 和 c-; 然而，IL-3 信号转导下的转录调控尚未完全阐明。本研究评估了核因子-κB 激酶 (IKK) 抑制剂在诱导 IL-3 介导的 IEG 表达中的作用。我们表明 IKK1 和 IKK2 是 IL-3 诱导小鼠造血 Ba/F3 细胞中 c-和 c-即刻表达所必需的。尽管 IKK2 作为经典核因子-κB (NF-κB) 途径的调节剂而广为人知，但 IKK 的激活并未诱导 NF-κB 转录因子的核易位。我们进一步揭示了 IKK2 在激活 c-Jun N 端激酶 (JNK) 中的重要作用，JNK 介导 IL-3 诱导的 c-和 c-表达。这些发现表明 IKK2-JNK 轴以不依赖经典 NF-κB 的方式调节 IL-3 诱导的 IEG 表达。
