Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B.
Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B.
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DOI：
10.3389/fphys.2023.1323865
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发表时间：
2023
影响因子：
4
通讯作者：
Reznikov LR
中科院分区：
文献类型：
--
作者：
Sponchiado M;Bonilla AL;Mata L;Jasso-Johnson K;Liao YJ;Fagan A;Moncada V;Reznikov LR
介绍：俱乐部细胞是粘液产生杯状细胞的前体。白细胞介素1β（IL-1B）是一种具有前粘蛋白活性的炎症介质，可增加产生粘液的杯状细胞的数量。肺泡腺癌细胞中IL-1B介导的粘蛋白产生需要cAMP反应元件结合蛋白（CREB）的激活。IL-1B的前粘蛋白活性是否需要俱乐部细胞CREB是未知的。 方法：我们用条件性丧失俱乐部细胞Creb 1的雄性小鼠和用气道内IL-1B或溶剂的野生型同窝小鼠进行攻击。其次，我们研究了人类“俱乐部细胞样”H322细胞。 结果：IL-1B增加全肺分泌型粘蛋白（Mucin 5ac，Mucin 5 b）和栓系型粘蛋白（Mucin 1，Mucin 4）的mRNA，与基因型无关。然而，俱乐部细胞Creb 1的缺失增加了RAS癌基因家族成员（Rab 3D）的全肺mRNA，降低了毒蕈碱受体3（M3 R）的mRNA，并阻止了IL-1B介导的嘌呤能受体P2 Y（P2 ry 2）mRNA的增加。IL-1B增加了野生型小鼠中含有中性粘蛋白的杯状细胞的密度，但在缺失俱乐部细胞Creb 1的小鼠中没有。这些结果表明，俱乐部细胞Creb 1调节粘蛋白分泌。棒状细胞Creb 1的缺失也可以防止IL-1B介导的气道力学损伤。在H322细胞中，4天的CREB药理学抑制增加了叉头框A2（FOXA 2）（杯状细胞扩增的阻遏物）的mRNA丰度，并降低了SAM指向结构域包含ETS转录因子（SPDEF）（杯状细胞扩增的驱动因子）的mRNA表达。染色质免疫沉淀表明，CREB直接结合到FOXA 2的启动子区，但不结合到SPDEF的启动子区。用IL-1B处理H322细胞增加cAMP水平，提供了IL-1B和CREB信号传导之间的直接联系。 结论：我们的研究结果表明，俱乐部细胞Creb 1调节IL-1B的前粘蛋白的性质，通过可能涉及FOXA 2的途径。
Introduction: Club cells are precursors for mucus-producing goblet cells. Interleukin 1β (IL-1B) is an inflammatory mediator with pro-mucin activities that increases the number of mucus-producing goblet cells. IL-1B-mediated mucin production in alveolar adenocarcinoma cells requires activation of the cAMP response element-binding protein (CREB). Whether the pro-mucin activities of IL-1B require club cell CREB is unknown. Methods: We challenged male mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-1B or vehicle. Secondarily, we studied human “club cell-like” H322 cells. Results: IL-1B increased whole lung mRNA of secreted (Mucin 5ac, Mucin 5b) and tethered (Mucin 1, Mucin 4) mucins independent of genotype. However, loss of club cell Creb1 increased whole lung mRNA of member RAS oncogene family (Rab3D), decreased mRNA of the muscarinic receptor 3 (M3R) and prevented IL-1B mediated increases in purinergic receptor P2Y, (P2ry2) mRNA. IL-1B increased the density of goblet cells containing neutral mucins in wildtype mice but not in mice with loss of club cell Creb1. These findings suggested that club cell Creb1 regulated mucin secretion. Loss of club cell Creb1 also prevented IL-1B-mediated impairments in airway mechanics. Four days of pharmacologic CREB inhibition in H322 cells increased mRNA abundance of forkhead box A2 (FOXA2), a repressor of goblet cell expansion, and decreased mRNA expression of SAM pointed domain containing ETS transcription factor (SPDEF), a driver of goblet cell expansion. Chromatin immunoprecipitation demonstrated that CREB directly bound to the promoter region of FOXA2, but not to the promoter region of SPDEF. Treatment of H322 cells with IL-1B increased cAMP levels, providing a direct link between IL-1B and CREB signaling. Conclusion: Our findings suggest that club cell Creb1 regulates the pro-mucin properties of IL-1B through pathways likely involving FOXA2.
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DOI：
10.1016/j.jcf.2016.05.002
发表时间：
2016-11
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
--
作者：
Darrah RJ;Mitchell AL;Campanaro CK;Barbato ES;Litman P;Sattar A;Hodges CA;Drumm ML;Jacono FJ
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影响因子：
4.4
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Kaestner KH
影响因子：
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作者：
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Yoon, Joo-Heon
DOI：
10.1165/rcmb.2006-0116oc
发表时间：
2007-01-01
影响因子：
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作者：
Bry, Kristina;Whitsett, Jeffrey A.;Lappalainen, Urpo
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