Cigarette smoke extract enhances neutrophil elastase-induced IL-8 production via proteinase-activated receptor-2 upregulation in human bronchial epithelial cells

Abstract

Although inflammation, oxidative stress, and protease-antiprotease imbalance have been referred to as a pathogenic triad in chronic obstructive pulmonary disease (COPD), little is known about how they interact. The objectives of this study were to elucidate the effect of cigarette smoke extract (CSE) on the neutrophil elastase (NE)-induced inflammatory response and its molecular mechanism in bronchial epithelial cells. We observed that NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation using a MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and knockdown of proteinase-activated receptor 2 (PAR2) using siRNAs inhibited both NE-induced ERK activation and subsequent IL-8 release, suggesting that NE-induced IL-8 production is dependent on PAR2-mediated ERK activation. Interestingly, pre-exposure to CSE markedly enhanced NE-induced IL-8 production. As PAR2 acts as a receptor for NE, we next investigated the effect of CSE on PAR2 expression as a molecular mechanism for the increased IL-8 production induced by NE in CSE exposed cells. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAPK reduced PAR2 expression induced by CSE while inhibition of the ERK and Akt pathway had no effect. Consequently, p38 inhibition significantly abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Of note, we observed increased PAR2 levels in lung homogenates and lung epithelial cells from CSE-treated mice and from both smokers and patients with COPD. Taken together, these results suggest that CSE upregulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE.

Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A–Induced Production of IL-36γ in Tonsillar Epithelial Cells

“…Our results also revealed that the costimulation of human epithelial cells with CSE þ IL-17A significantly increased the production of IL-17Aeinduced cytokines via an upregulation of IL-17R (Figures 2a and 3), which is consistent with a previous report (Lee et al, 2018). In another study, the IL-17A pathway was activated in the skin lesions of PPP (Bissonnette et al, 2017).…”

Characteristics of Japanese patients with pustulotic arthro‐osteitis associated with palmoplantar pustulosis: a multicenter study

“…In total, 165 patients with PAO were identified among 576 patients with PPP (28.6%). There were 35 males (21.2%) and The most common location of pain was the anterior chest (n = 134), followed by shoulder (34), lumbar spine (19), knee (14), cervical spine (11), digit (9), ankle (9), sacroiliac joint (8), elbow (5), wrist (5), mandible (2), back (2), sole (1), and heal (1). Technetium bone scintigraphy was performed in 97 cases (97/165: 58.8%).…”

“…AhR activation contributes to Th17 differentiation through various intracellular signaling pathways . In addition, cigarette smoke extracts enhanced IL‐17A‐induced IL‐8 production by human bronchial epithelial cells, mediated by upregulation of IL‐17 receptor expression . Thus, Th1/Th17‐type cytokine balance is suggested to play an important role in the pathogenesis of PPP …”

Pistacia weinmannifolia ameliorates cigarette smoke and lipopolysaccharide‑induced pulmonary inflammation by inhibiting interleukin‑8 production and NF‑κB activation

“…The high level of neutrophil influx is understood to be a typical characteristic of COPD (56). Neutrophils release a protease that causes damage to the endothelial cells of the airway and accelerates lung destruction (57). Neutrophil-derived ROS lead to oxidative stress in the pathogenesis of lung inflammation and are consistently observed in patients with COPD and COPD animal models (58).…”