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

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 and 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 duanyu18136 and Pharmacological inhibition of the UPR sensor IRE1α blocks cathepsin secretion and blunts macrophage-mediated cancer cell invasion. Similarly, genetic deletion of duanyu18133 and duanyu18136 signaling components impairs tumor development and invasion in vivo. Together, these findings demonstrate that cytokine-activated duanyu18133 and duanyu18136 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsin-dependent manner. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

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