AdipoR-increased intracellular ROS promotes cPLA₂and COX-2 expressions via activation of PKC and p300 in adiponectin-stimulated human alveolar type II cells

Abstract

Adiponectin, an adipokine, accumulated in lung system via T-cadherin after allergens/ozone challenge. However, the roles of adiponectin on lung pathologies were controversial. Here we reported that adiponectin stimulated expression of inflammatory proteins, cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and production of reactive oxygen species (ROS) in human alveolar type II A549 cells. AdipoR1/2 involved in adiponectin-activated NADPH oxidase and mitochondria, which further promoted intracellular ROS accumulation. Protein kinase C (PKC) may involve an adiponectin-activated NADPH oxidase. Similarly, p300 phosphorylation and histone H4 acetylation occurred in adiponectin-challenged A549 cells. Moreover, adiponectin-upregulated cPLA2 and COX-2 expression was significantly abrogated by ROS scavenger (N-acetylcysteine) or the inhibitors of NADPH oxidase (apocynin), mitochondrial complex I (rotenone), PKC (Ro31-8220, Gö-6976, and rottlerin), and p300 (garcinol). Briefly, we reported that adiponectin stimulated cPLA2 and COX-2 expression via AdipoR1/2-dependent activation of PKC/NADPH oxidase/mitochondria resulting in ROS accumulation, p300 phosphorylation, and histone H4 acetylation. These results suggested that adiponectin promoted lung inflammation, resulting in exacerbation of pulmonary diseases via upregulating cPLA2 and COX-2 expression together with intracellular ROS production. Understanding the adiponectin signaling pathways on regulating cPLA2 and COX-2 may help develop therapeutic strategies on pulmonary diseases.

Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

“…For example, lung epithelial cells of cystic fibrosis (CF) patients have elevated cPLA 2 activity and produce more eicosanoids than do normal epithelial cells (73). Activation of cPLA 2 via phosphorylation is imperative for the production of eicosanoids and is dependent on MAP kinases and protein kinase C (PKC) (42,50,74), and we found that phosphorylated cPLA 2 accumulated in the membrane fraction of lung epithelial cells after pneumococcal infection.…”

Contrasting Effects of Adipokines on the Cytokine Production by Primary Human Bronchial Epithelial Cells: Inhibitory Effects of Adiponectin

“…In studies with A549 cells, AdipoR1 (but not AdipoR2) was strongly expressed after stimulation with TNF-a (as assessed with RT-PCR, immunohistochemistry, and Western Blot), whereas unstimulated A549 cells did not express AdipoR1 (Miller et al, 2009). In two different studies, the two subtypes of AdipoRs were found to be expressed at the mRNA and protein levels in A549 cells and in two other human lung cell lines (SW-1573 and Calu-3) (Chen et al, 2016;Cheng et al, 2016). However, an immunohistochemistry study of lung sections from patients with COPD demonstrated that airway epithelial cells expressed significant levels of AdipoR1 but not of AdipoR2 (Miller et al, 2009).…”

“…However, in Nigro et al's study (Nigro et al, 2013) of the same cell line, incubation with full-length APN (5 or 50 µg.ml -1 for 14 h) did not influence the mRNA expression of CXCL-8, CCL-2, and IL-6. Furthermore, Chen et al reported that full-length APN upregulated cytosolic phospholipase A2 and cyclooxygenase-2 in the A549 cell line (Chen et al, 2016). The A549 cell line is a hypotriploid human cell line initiated by the explant culture of lung carcinomatous tissue.…”

Adiponectin-Based Therapeutics for Cancer Treatment

“…However, the phenotypes of adiponectin-deficient mice have not been thoroughly replicated by the AdipoR1/R2 dual-deficient mice [116]. Moreover, a number of studies have suggested a pro-inflammatory role of AdipoR1/R2 [135,136]. AdipoR1 and AdipoR2, as well as other members of the progestin and AdipoQ receptor superfamily, possess potent ceramidase activities to produce ceramide and phosphorylated sphingoid, which are causatively involved in the development of insulin resistance, atherosclerosis and heart failure [137 -140].…”