Nintedanib Prevents IL-6-mediated Secretion of CCL-18 in Alternatively Activated Macrophages and Transition of Fibroblasts to Myofibroblasts
Mechanisms of Lung Injury and Repair(2017)
Abstract
Background: The pathogenesis of idiopathic pulmonary fibrosis (IPF) is incompletely understood. Recent data suggest a role of alternatively activated macrophages (Mφ) on the transition of fibroblasts to myofibroblasts (FMT) and accumulation of extracellular matrix proteins. Nintedanib (NI) is a tyrosine kinase inhibitor approved for the treatment of IPF. Aim: We investigated the effect of NI on Mφ polarization and its effect in preventing Mφ-mediated FMT. Methods: Naïve Mφ differentiated from human THP-1 were examined for alternative activation by IL-4/-13 or IL-4/-13/-6 exposure ± NI (0.1 - 0.3 µM). Secreted CCL-18 was assessed to confirm alternative activation. In addition, IL-4/-13/-6 hyper-activated Mφ treated ± NI were co-cultured with primary lung fibroblasts and assessed for aSMA expression to confirm FMT. Recombinant CCL-18 and TGFb were used to examine their effect on FMT. Results: The addition of IL-6 to the conventional Mφ polarization cocktail IL-4/-13 resulted in a significant increase in CCL-18 compared to IL-4/-13 exposed alone (5.3 ± 1.3 vs 0.5 ± 0.09 ng/mL; mean ± SD). NI prevented the release of CCL18. The IL-6 hyper-polarized Mφ were shown to trigger FMT, which NI prevented. The addition of CCL-18 to TGFb resulted in a synergistic increase in FMT, while CCL-18 alone had no effect. Conclusion: Nintedanib prevents IL-6-mediated CCL-18 secretion and subsequent myofibroblast transition in vitro. These results suggest that the antifibrotic effect of nintedanib observed in IPF patients may be associated with its effect on reducing CCL-18 secretion by alternatively activated macrophages.
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