Inhibition of IL‐13‐induced periostin in airway epithelium attenuates cellular protein expression of MUC5AC

Abstract

Background and objective: Serum periostin is increased in asthma and serves as a surrogate marker for IL-13 activity in the lung. Serum levels of periostin are the most robust biomarker predicting a favourable response to the anti-IL-13 drug, lebrikizumab. We investigated the mechanisms of IL-13 stimulation of periostin, the polarized secretion of periostin and whether periostin would have a direct effect on mucin secretion by airway cells. Methods: Normal human bronchial epithelial (NHBE) cells were cultured at air-liquid interface (ALI) in the presence of IL-13, and we evaluated the effect of the specific inhibitors, leflunomide (Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) inhibitor) or PD98059 (MEK/extracellular regulated protein kinase (ERK) inhibitor), on periostin production. We examined MUC5AC secretion from NHBE cells exposed to recombinant human (rh) periostin or IL-13 in the presence and absence of OC-20, a periostin-neutralizing antibody. Results: IL-13 induced periostin protein which was predominantly secreted towards the basal surface of the cells. Periostin production was much greater from goblet cells than ciliated cells (P < 0.001). Periostin production after exposure to IL-13 was attenuated by both leflunomide (P < 0.001) and PD98059 (P < 0.001). The addition of exogenous periostin modestly increased MUC5AC secretion (P < 0.01), but did not visibly change cell morphology. IL-13-induced MUC5AC secretion was attenuated by OC-20 (P < 0.01). Conclusion: Periostin production in differentiated airway cells is mediated by JAK/STAT6 and MEK/ERK pathways. Periostin secretion is much greater from immunologically active goblet cells. IL-13-driven mucin production is partially inhibited by OC-20.

Mechanism of Periostin Production in Human Bronchial Smooth Muscle Cells

“…Furthermore, STAT6 siRNA decreased periostin expression in lung fibroblasts [24]. Subsequently, the ERK1/2 pathway, as well as the JAK/STAT6 pathway, has also been shown to be important for periostin production in human airway epithelial cells cultured at an air-liquid interface [25] and in human lung fibroblasts [26]. Furthermore, other studies demonstrated that in vascular smooth muscle cells, the PI3K/Akt and ERK1/2 pathways, rather than the JAK/STAT6 pathway, are important for producing periostin [27,28].…”

Year in review 2017: Chronic obstructive pulmonary disease and asthma

“…81 Although inhibition of periostin attenuated IL-13-driven MUC5AC mucin production, periostin only weakly stimulated mucus secretion. 81…”

“…Furthermore, it was observed that simvastatin, a 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor, partially attenuated airway inflammation and reversed the overabundance of bronchial smooth muscle cells, thereby ameliorating AHR through an activated autophagic process in ovalbumin‐sensitized and ‐challenged murine models of asthma . Finally, Suzaki et al . investigated the use of a periostin‐neutralizing antibody in differentiated airway epithelial cells.…”

“…investigated the use of a periostin‐neutralizing antibody in differentiated airway epithelial cells. IL‐13‐induced periostin production was found to be regulated by Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) and MEK/extracellular regulated protein kinase (ERK) pathways . Although inhibition of periostin attenuated IL‐13‐driven MUC5AC mucin production, periostin only weakly stimulated mucus secretion …”

“…79 Furthermore, it was observed that simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, partially attenuated airway inflammation and reversed the overabundance of bronchial smooth muscle cells, thereby ameliorating AHR through an activated autophagic process in ovalbumin-sensitized and -challenged murine models of asthma. 80 Finally, Suzaki et al 81 investigated the use of a periostinneutralizing antibody in differentiated airway epithelial cells. IL-13-induced periostin production was found to be regulated by Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) and MEK/extracellular regulated protein kinase (ERK) pathways.…”