IL-1β dysregulates cGMP signaling in the newborn lung

Abstract

Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1β regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1β were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1β treatment did not alter sGCα1 mRNA stability, although it reduced sGCα1 promoter activity. Transforming growth factor-β (TGFβ)-activated kinase-1 (TAK1) was determined to be required for IL-1β’s regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1β-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-κB (NF-κB) signaling played a critical role in the IL-1β-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-κB subunit (RelA) binding to the sGCα1 promoter after IL-1β treatment unless treated with an IκB kinase-2 inhibitor. Also, this NF-κB signaling inhibition protected sGCα1 expression in IL-1β-treated fibroblasts. Lastly, using transgenic mice in which active IL-1β was conditionally expressed in lung epithelial cells, we established that IL-1β expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1β inhibits cGMP signaling in the newborn lung.

miR-218-5p Induces Interleukin-1β and Endovascular Trophoblast Differentiation by Targeting the Transforming Growth Factor β-SMAD2 Pathway

“…Therefore, we explored the role of IL1β in the induction of an enEVT-like phenotype. We used recombinant IL1β at concentrations of 1 pg/ml–10 ng/ml in functional assays, a dosage range commonly used in previous studies ( 32 , 48 , 49 ). We found that IL1β enhanced the ability of trophoblasts to form endothelial-like network structures starting from 1 pg/ml ( Figure 6A ).…”

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

“…In addition, decreased expression of the sGC enzyme has been observed in alveolar and bronchial epithelial cells and in airway smooth muscle cells in COPD patients and smokers (Glynos et al, 2013;Weissmann et al, 2014), as well as in asthmatic patients and animal models of asthma (Papapetropoulos et al, 2006;London et al, 2018). The underlying mechanism is not well understood but recently, it has been shown that the expression of the α1 subunit of sGC is downregulated by TGF-β in pulmonary artery smooth muscle cells via MEK and ERK signaling (Du and Roberts, 2019) and IL-1β in perinatal lung fibroblasts via TAK1 and NF-κB signaling (Zhong et al, 2020) and both inflammatory mediators are increased in COPD and asthma disease so they FIGURE 3 | Schematic view of T2 eosinophilic airway inflammation in the pathophysiology of asthma. Allergens or epithelial damage activates dendritic cells that secrete cytokines, such as IL-4, leading to Th2 differentiation.…”

NO‐sensitive guanylyl cyclase in the lung

“…The underlying mechanisms are not well defined, but several cytokines appear to be involved. Transforming growth factor β (TGFβ) and IL‐1β were shown to downregulate the α 1 subunit of NO‐GC in rat pulmonary artery smooth muscle cell via MEK/ERK or NF‐κB signalling, respectively (Du & Roberts, 2019; Zhong, Bry, & Roberts, 2020). Other mechanisms that promote downregulation of NO‐GC subunits include microRNAs (Xu et al, 2012) and H 2 O 2 (Wedgwood et al, 2005).…”