Interferon-γ enhances phorbol myristate acetate-induced cell attachment and tumor necrosis factor production via the NF-κB pathway in THP-1 human monocytic cells

During inflammation, activated macrophages express adhesion molecules and produce cytokines that interact with other hematopoietic and stromal cells. THP-1 non-adherent human monocytic cells differentiate into plastic-adherent macrophages via alpha(nu)beta(3) integrin, by ERK activation in the presence of phorbol myristate acetate (PMA). This has proven to be a valuable model for investigating functional monocyte/macrophage diversity. Interferon-gamma (IFN-gamma) is a Th1-cytokine that is crucial in macrophage activation. In this study, we investigated the effects of IFN-gamma on adhesion and the secretion of tumor necrosis factor (TNF) by PMA-stimulated THP-1 cells. IFN-gamma is incapable of inducing cell attachment and TNF production; however, it cumulatively upregulated PMA-induced basal adhesion and TNF production. IFN-gamma increased alpha(nu) integrin, ICAM-1 and VCAM-1 expression and among these PMA-induced cell surface adhesion molecules, the blocking antibody for alpha(v) integrin suppressed adhesion and TNF production. Furthermore, IFN-gamma enhanced PMA-induced NF-kappa B phosphorylation and not ERK phosphorylation. Accordingly, the NF-kappa B pathway inhibitor (BAY 11-7082) inhibited the enhancing effect of IFN-gamma on adhesion and TNF production. By contrast, the MEK inhibitor (U0126) almost completely eliminated PMA-induced basal adhesion and TNF production. In conclusion, IFN-gamma regulates macrophage activation by mediating the NF-kappa B signaling pathway.