Osteopontin (Eta-1, early T lymphocyte activation protein-1) is an acidic glycoprotein that binds to adhesion molecules such as CD44 and certain integrins. It is secreted by activated T cells as well as macrophages.1 Osteopontin has diverse biological functions, including induction of macrophage migration, the proliferation of B cells and Ig production. Osteopontin is also involved in crescentic glomerulonephritis2 and granuloma formation in tuberculosis and silicosis.3
Cytokines secreted during cell-mediated/type 1 (Th1) immune responses can promote granuloma formation. Macrophage production of IL-12 provokes a Th1 response, stimulating NK cells, cytotoxic T cell activity and macrophage activity via IFN-gamma. IL-12 activity prevents the development of a humoral/type 2 (Th2) immune response. Absence of IL-10 during a Th1 response enhances granuloma development.
A mouse model of granulomatous disease can be induced by injection with polyvinyl pyrrolidone (PVP). Nude mice cannot develop granulomas when injected with PVP. If osteopontin is co-injected with PVP, however, the mice display a granulomatous reaction.4 Similarly, osteopontin-deficient mice fail to develop a granulomatous reaction when injected with PVP, but a response can be partially restored by injection with osteopontin.
Mice deficient in osteopontin gene expression have an impaired Th1 response to viral and bacterial infections and do not develop granulomas. Production of IL-12 and IFN-gamma within these mice is diminished while the level of IL-10 is increased. Osteopontin appears to play a key role in their Th1 response. A phosphorylation-dependent interaction between the amino-terminus of osteopontin and its integrin receptor stimulates IL-12 expression, while a phosphorylation-independent interaction with CD44 inhibits IL-10 expression.4 Osteopontin may facilitate granuloma formation during a cell-mediated/Th1 immune response by regulating IL-12 and IL-10 expression.