creb regulates tnf-α-induced gm-csf secretion via p38 mapk in human lung fibroblasts

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ID: 190033
2016
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Abstract
Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that mediates eosinophilic differentiation, migration and survival, causing respiratory tract inflammation. GM-CSF is also known to be secreted from respiratory tract structural cells. However, the mechanisms of GM-CSF secretion have not been well established. Methods: Human fetal lung fibroblasts and human primary asthmatic lung fibroblasts were used for the study of tumor necrosis factor alpha (TNF-α)-induced GM-CSF secretion. GM-CSF secretion and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative real-time reverse transcription polymerase chain reaction, respectively. Knockdown of cAMP response element-binding protein (CREB) in fibroblasts was carried out by using specific small interfering RNAs of CREB. Results: Among respiratory tract structural cells, pulmonary fibroblasts exhibited increased GM-CSF secretion and mRNA expression after stimulation with TNF-α in a concentration-dependent manner. Moreover, a p38 mitogen-activated protein kinase (MAPK) inhibitor controlled TNF-α-induced GM-CSF secretion, and roflumilast and rolipram, inhibitors of phosphodiesterase-4, suppressed TNF-α-induced GM-CSF secretion. Consistent with this, forskolin also completely blocked GM-CSF secretion, and similar results were observed in response to cAMP treatment, suggesting that cAMP signaling suppressed TNF-α-induced GM-CSF secretion in human lung fibroblasts. Furthermore, CREB was phosphorylated through p38 MAPK but not cAMP signaling after TNF-α stimulation, and GM-CSF secretion was inhibited by CREB knockdown. Finally, these effects were also demonstrated in human primary lung fibroblasts in a patient with asthma. Conclusions: CREB signaled independent of cAMP signaling and was phosphorylated by p38 MAPK following TNF-α stimulation, playing a critical role in GM-CSF secretion in human lung fibroblasts.
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koga2016allergologycreb Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Yasuhiko Koga, Takeshi Hisada, Tamotsu Ishizuka, Mitsuyoshi Utsugi, Akihiro Ono, Masakiyo Yatomi, Yosuke Kamide, Haruka Aoki-Saito, Hiroaki Tsurumaki, Kunio Dobashi, Masanobu Yamada
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Journal current drug discovery technologies
Year 2016
DOI
10.1016/j.alit.2016.03.006
URL
http://www.sciencedirect.com/science/article/pii/S1323893016300284
Keywords
asthma gm-csf camp creb allergy

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