28 ER stress and TLR activation inter-regulate through p65, p38, STAT3, and XBP1s to modulate inflammation in cystic fibrosis

Abstract

Background There is increasing appreciation for the inflammatory role of ER stress in a spectrum of diseases. Previous work showed increased ER stress responses in airway epithelial cells, blood cells, and lung tissue from patients with cystic fibrosis (CF) [1]. Although its role in disease progression is unclear, there are many potential sources of ER stress in CF airways including misfolded CFTR, pathogens, and oxidizing conditions, which can increase inflammation and subsequent damage. Objectives To determine the specific mechanisms through which ER stress regulates inflammation in CF. Methods CF airway cells (IB3–1, CuFi-1), ΔF508-transfected A549 cells, and monocytic cells (THP-1) were used to determine ER stress/inflammatory pathway interactions. Signaling was examined by cell fractionation, immunoblot, and reporter assays, and inflammatory output by qPCR and ELISA. Results ER stressors alone increased cytokine mRNA but not NF-κB activation or cytokine secretion. However, ER stress in conjunction with subsequent TLR stimulation significantly augmented IL-6, IL-8, and IL-1β levels (P Conclusion ER stress sensitizes inflammatory pathways to TLR stimulation and drives XBP1s-mediated cytokine production. ER stress inhibition has potential therapeutic value in decreasing excessive inflammatory responses.