On the surface of the macrophage, annexin A2 tetramer (A2t) serves as a docking protein or recognition element for bacterial and viral pathogens. Plasma levels of free A2t have been reported to increase following infection, although the mechanistic significance of this observation is unclear. Although annexin A2 had generally been thought to play an anti-inflammatory role, soluble A2t stimulates MAP kinase activity in bone marrow stromal cells downstream of a recently cloned receptor. This raises the question of whether A2t activates human macrophages via MAP kinases and whether it might be capable of acting as an inflammatory mediator. To this end, human monocyte-derived macrophages were treated with soluble A2t and MAP kinase phosphorylation, p65 NF-kappaB activation, and inflammatory mRNA and protein levels were measured. It was found that A2t caused rapid phosphorylation of several MAP kinases, as well as translocation of p65 NF-kappaB to the nucleus. A2t stimulated the production of TNF-alpha, IL-1beta, and IL-6, as well as several members of the chemokine family within 24 h, which are capable of recruitment and/or activation of a broad range of leukocyte classes. Furthermore, A2t-activated macrophages demonstrated enhanced phagocytic ability for the ingestion of GFP-expressing Escherichia coli. These data are the first to suggest the participation of an annexin in microbial clearance, as well as the establishment of inflammation and the immune response, including the recruitment and activation of immune cells to the site of infection.