Angiocidin was originally identified as a potent inhibitor of angiogenesis and tumor growth in vivo. In addition to its involvement in the regulation of carcinogenesis, recent studies indicate that angiocidin may also play a significant role in immune system modulation. This report describes the expression and potential function of angiocidin in multiple sclerosis (MS), a severe demyelinating, inflammatory and autoimmune disease of the central nervous system (CNS). We demonstrated that angiocidin and interleukin-7 (IL-7) are over-expressed in brain lesions of MS patients. Angiocidin-treated monocytes, peripheral blood T cells and primary astrocytes secreted various cytokines and chemokines including, IL-6, IL-7, GM-CSF, and MCP-1. Addition of recombinant angiocidin to cell cultures was able to promote differentiation of monocytes into a macrophage-like cell, induce MHC class I and class II gene expression and activate CD4(+) and CD8(+) T lymphocytes. Consistent with these findings, angiocidin induced mononuclear phagocyte migration and adhesion as well as increased the IL-2 response by antigen-specific T cells to myelin basic protein peptide presented to them by autologous mononuclear phagocytes. Furthermore, we examined STAT3 expression in angiocidin stimulated mononuclear phagocytes, T cells, and primary astrocytes. We found that angiocidin markedly stimulates STAT3 expression in these cell populations. Angiocidin, therefore appears to play a previously unappreciated and potentially important role in the regulation of immune response during the clinical course of MS.