TY - JOUR T1 - LATE-BREAKING ABSTRACT: Inhibition of MAP3K19 - A novel therapeutic approach for treatment of IPF JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2015.PA4374 VL - 46 IS - suppl 59 SP - PA4374 AU - Stefen Boehme AU - Tai Wei Ly AU - Kevin Bacon Y1 - 2015/09/01 UR - http://erj.ersjournals.com/content/46/suppl_59/PA4374.abstract N2 - MAP3K19 (RC Kinase) is a novel nuclear kinase that is expressed in healthy lung by macrophages and type II epithelial cells, upregulated in IPF lungs, and commonly found in atypical epithelium adjacent to fibroblastic foci. Consistent with this cellular distribution, late-stage pre-clinical small molecule inhibitors of MAP3K19 caused significant reductions in inflammatory infiltrate, extra-cellular matrix deposition and hydroxyproline production in a murine xenograft model of IPF. In the murine bleomycin model, prophylactic or therapeutic oral administration of a MAP3K19 antagonist compound significantly decreased inflammation, fibrosis and collagen content. In contrast, Pirfenidone only significantly affected lung collagen levels. To understand the mechanism of action of specific MAP3K19 inhibitors, we examined whether the TGF-β signaling pathway was impacted. An examination of IPF patient-derived myofibroblast cell lines, primary human macrophages, and numerous MAP3K19+ human cell lines showed that inhibition of MAP3K19 resulted in a significant decrease in the nuclear accumulation of P-Smad-2 and P-Smad-3 upon TGF-β stimulation. Pirfenidone had minimal effects. Inhibition of MAP3K19 did not affect Smad-4 levels, and cytoplasmic levels of Smad-2 and Smad-3 were also unaffected. Inhibition of MAP3K19 also blocked TGF-β-induced gene transcription of various EMT molecules. Surprisingly, inhibition of MAP3K19 also inhibited TGF-β-induced nuclear translocation of Notch. These results suggest that MAP3K19 may act as a regulator of nuclear translocation of various signaling molecules involved in transcription, and provides a mechanism to explain how MAP3K19 inhibition may provide therapeutic benefit in IPF. ER -