Wnt5a activates THP-1 monocytic cells via a β-catenin-independent pathway involving JNK and NF-κB activation

► Hypoxia activates monocytic THP-1 cells to express Wnt5a. ► Wnt5a rapidly induces CXC chemokines and pro-inflammatory cytokines in THP-1 cells. ► Wnt5a activates THP-1 cells via β-catenin-independent Wnt signaling. ► Wnt5a activates NF-κB and JNK in THP-1 cells. ► Wnt5a-induced NF-κB activation is JNK-dependent. Wnt5a has been implicated in the activation of macrophages. However, the profile and mechanism of downstream regulation has not been characterized. In this study, we have investigated the regulation of Wnt5a-induced activation in monocytic THP-1 cells. Wnt5a activated THP-1 cells, enhancing adhesion to endothelial cells. Hypoxia induced the production of Wnt5a, suggesting a role in the hypoxia-induced activation of macrophages. Wnt5a induced the expression of various pro-inflammatory cytokines and inflammatory mediators, particularly IL8 and CXCL2, suggesting a major role in the secretion of CXC chemokines by macrophages. Wnt5a induced JNK phosphorylation and NF-κB activation via β-catenin-independent signaling. Interestingly, SP600125, a specific inhibitor of JNK, inhibited Wnt5a-induced activation of NF-κB, supporting JNK-dependent NF-κB activation. Our data suggest that Wnt5a activates monocytic cells via JNK and NF-κB activation.