Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway

Abstract

Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER stress markers in the lung. Furthermore, inhibition of ER stress reduced the LPS-induced lung inflammation. Moreover, LPS-induced increases of NF-κB and HIF-1α activity were lowered by inhibition of ER stress. These results suggest that inhibition of ER stress ameliorates LPS-induced lung inflammation through modulation of NF-κB/IκB and HIF-1α signaling pathway.

Crosstalk Between Nuclear Glucose-Regulated Protein 78 and Tumor Protein 53 Contributes to the Lipopolysaccharide Aggravated Apoptosis of Endoplasmic Reticulum Stress-Responsive Porcine Intestinal Epithelial Cells

“…Because this outcome differed from that previously reported from in-vivo examinations, we might speculate that cell cultures treated with TUNI alone either cannot trigger or they lack the activation factor that initiates inflammation. When ERS is induced by TUNI, it can trigger the upregulation of cytoplasmic GRP78 and the PERK-CHOP pathway [59,60], which is consistent with our results. We found that the inflammatory milieu induced by LPS promoted apoptosis in responsive cells and altered the subcellular localization of GRP78.…”

Silver Nanoparticles Induce Degradation of the Endoplasmic Reticulum Stress Sensor Activating Transcription Factor-6 Leading to Activation of the NLRP-3 Inflammasome

“…Moreover, tunicamycin was previously shown to induce ATF-6 degradation (7). Another study also demonstrates that inhibition of ER stress by sodium 4-phenylbutyrate results in a significant reduction in IL-1␤ levels, supporting the role of ER stress in IL-1␤ production (41). However, to the best of our knowledge, the role of ATF-6 in the activation of the NLRP-3 inflammasome had never been investigated before.…”

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…In another study focusing on diabetic nephropathy, it was suggested that 4-PBA could reduce the expression of the inflammatory transcription factor NFB by suppressing oxidative stress (Luo et al, 2010). Another group also suggests that 4-PBA can attenuate LPS-induced inflammation through modulation of the NFB pathway (Kim et al, 2013). In a study modeling hypoxia in glial cells, 4-PBA was able to reduce ER stress induced inflammation as measured by TNF␣ (Qi et al, 2004).…”