Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal interstitial lung disease characterized by consistent pulmonary inflammation. Although protein kinase C delta (PKCδ) is involved in broad scope cellular response, the role of PKCδ in IPF is complicated and has not been fully defined yet. Here, we reported that PKCδ deficiency (PKCδ–/–) aggravated bleomycin (BLM)-induced pulmonary fibrosis and inflammation. Upon challenge with BLM, the pulmonary capillary permeability, immune cell infiltration, inflammatory cytokine production, and collagen deposition were enhanced in PKCδ–/– mice compared to that in PKCδ+/+ mice. In response to poly(I:C) stimulation, PKCδ deficient macrophages displayed an increased production of IL-1β, IL-6, TNF-α, and IL-33, which were associated with an enhanced NF-κB activation. Furthermore, we found that PKCδ could directly bind to and phosphorylate A20, an inhibitory protein of NF-κB signal. These results suggested that PKCδ may inhibit the NF-κB signaling pathway via enhancing the stability and activity of A20, which in turn attenuates pulmonary fibrosis, suggesting that PKCδ is a promising target for treating pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive, devastating, and lethal interstitial lung disease
PKCδ has been reported to be involved in the progression of pulmonary fibrosis, the role of PKCδ in IPF is still under controversy
PKCδ phosphorylation was significantly increased in lung tissue of patients with pulmonary fibrosis and the PKCδ deficiency enhanced BLM-induced inflammation and pulmonary fibrosis, suggesting that PKCδ plays a protective role in IPF
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive, devastating, and lethal interstitial lung disease. It has a prevalence of 7∼10 per 100,000 people worldwide and a mean survival of only 3∼4 years since diagnosis (Dempsey, 2006). Characterized by inflammation, fibroblast accumulation, and extracellular matrix deposition, pulmonary fibrosis eventually leads to the disruption of lung architecture that hinders blood gas exchange (Nie et al, 2017). Since the etiology and mechanism of IPF have not been fully unveiled (Desai et al, 2018) and current therapies have limited efficacy (Fujimoto et al, 2015), it is vital that new drug targets are to be identified as treatment options for the management and resolution of IPF. The etiology of pulmonary fibrosis is complicated and unclear, inflammation is definitively involved in pathogenesis of IPF (Bringardner et al, 2008). Damaged tissue releases various inflammatory stimuli from the nucleus or cytosol, such as high mobility group
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