Department of Biochemistry, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.
Center for Gene Therapy Research, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.
J Immunol. 2020 Apr 15;204(8):2033-2042. doi: 10.4049/jimmunol.1900315. Epub 2020 Mar 6.
IκBζ (encoded by the ) is a member of the nuclear IκB family, which is involved in the expression of secondary response genes based on signals from TLR or IL-1R. ST2L, an IL-33R, is a member of the IL-1R family and abundantly expressed in tissue-resident immune cells, such as mast cells and innate lymphoid cells; however, its downstream signaling pathway remains unelucidated. In this study, we examined the role of IκBζ in ST2L-mediated cytokine and chemokine production in mast cells. Murine bone marrow cells were differentiated ex vivo into bone marrow-derived mast cells (BMMCs). The treatment of BMMCs with IL-33 transiently induced robust IκBζ expression. Of the 40 cytokines and chemokines examined using a cytokine and chemokine array, the concentrations of IL-6, IL-13, CCL2, CCL3, and TNF-α in the supernatant were augmented by IL-33. The deletion of IκBζ in BMMCs resulted in a significant reduction of the production of these mediators and the expression of their mRNA. NF-κB p50 but not p65 translocated to the nucleus by IL-33 and was not affected by the deletion of IκBζ. However, induction of IκBζ and the resultant cytokine and chemokine productions were significantly inhibited by pretreatment with an NF-κB inhibitor. The deletion of IκBζ did not affect the phosphorylation of ERK, p38 MAPK, or JNK by IL-33, and the treatment with inhibitors of these mitogen-activated kinases failed to abolish the expression of Our findings suggest that IκBζ augments IL-33-dependent cytokine and chemokine production in BMMCs through the action of NF-κB.
IκBζ（由 编码）是核 IκB 家族的成员，该家族参与基于 TLR 或 IL-1R 信号的次级反应基因的表达。ST2L，一种 IL-33R，是 IL-1R 家族的成员，在组织驻留免疫细胞（如肥大细胞和固有淋巴细胞）中大量表达；然而，其下游信号通路仍不清楚。在这项研究中，我们研究了 IκBζ 在 ST2L 介导的肥大细胞细胞因子和趋化因子产生中的作用。从骨髓细胞中体外分化为骨髓来源的肥大细胞（BMMCs）。IL-33 短暂处理 BMMCs 会瞬时诱导强烈的 IκBζ 表达。在细胞因子和趋化因子阵列中检查的 40 种细胞因子和趋化因子中，IL-33 使上清液中 IL-6、IL-13、CCL2、CCL3 和 TNF-α 的浓度增加。BMMCs 中 IκBζ 的缺失导致这些介质的产生和其 mRNA 的表达显著减少。NF-κB p50 而不是 p65 通过 IL-33 易位到核内，并且不受 IκBζ 缺失的影响。然而，NF-κB 抑制剂的预处理显著抑制 IκBζ 的诱导和由此产生的细胞因子和趋化因子的产生。IκBζ 的缺失不影响 IL-33 对 ERK、p38 MAPK 或 JNK 的磷酸化，并且这些有丝分裂原激活的激酶的抑制剂的处理未能消除 我们的研究结果表明，IκBζ 通过 NF-κB 的作用增强了 BMMCs 中 IL-33 依赖性细胞因子和趋化因子的产生。
