STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation.

ABSTRACT: Tumor-associated macrophages play critical roles during tumor progression by promoting angiogenesis, cancer cell proliferation, invasion, and metastasis. Cysteine cathepsin proteases, produced by macrophages and cancer cells, modulate these processes, but it remains unclear how these typically lysosomal enzymes are regulated and secreted within the tumor microenvironment. Here, we identify a STAT3 and STAT6 synergy that potently upregulates cathepsin secretion by macrophages via engagement of an unfolded protein response (UPR) pathway. Whole-genome expression analyses revealed that the TH2 cytokine interleukin (IL)-4 synergizes with IL-6 or IL-10 to activate UPR via STAT6 and STAT3. Pharmacological inhibition of the UPR sensor IRE1α blocks cathepsin secretion and blunts macrophage-mediated

SUBMITTER: Yan D 

PROVIDER: S-EPMC5559199 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature