S 100 A 9 promotes human lung fibroblast cells activation through receptor for advanced glycation end‐product‐mediated extracellular‐regulated kinase 1/2, mitogen‐activated protein‐kinase and nuclear factor‐κ B ‐dependent pathways

Summary S 100 A 9 belongs to the S 100 family of calcium‐binding proteins and plays a key role in many inflammatory conditions. Recent studies have found that S 100 A 9 was elevated significantly in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients, and might be a biomarker for fibrotic interstitial lung diseases. However, the exact function of S 100 A 9 in pulmonary fibrosis needs further studies. We performed this study to investigate the effect of S 100 A 9 on human embryo lung fibroblast ( HLF ) proliferation and production of cytokines and collagen, providing new insights into the possible mechanism. S 100 A 9 promoted proliferation of fibroblasts and up‐regulated expression of both proinflammatory cytokines interleukin ( IL) ‐6, IL ‐8, IL ‐1β and collagen type III . S 100 A 9 also induced HLF cells to produce α‐smooth muscle actin (α‐ SMA ) and receptor for advanced glycation end‐product ( RAGE ). In addition, S 100 A 9 caused a significant increase in extracellular‐regulated kinase ( ERK) 1/2 mitogen‐activated protein kinase ( MAPK ) phosphorylation, while the status of p38 and c‐Jun N‐terminal kinase ( JNK) phosphorylation remained unchanged. Treatment of cells with S 100 A 9 also enhanced nuclear factor kappa B ( NF ‐κ B ) activation. RAGE blocking antibody pretreatment inhibited the S 100 A 9‐induced cell proliferation, cytokine production and pathway phosphorylation. S 100 A 9‐mediated cell activation was suppressed significantly by ERK 1/2 MAPK inhibitor and NF ‐κ B inhibitor. In conclusion, S 100 A 9 promoted HLF cell growth and induced cells to secret proinflammatory cytokines and collagen through RAGE signalling and activation of ERK 1/2 MAPK and NF ‐κ B pathways.