316 of IFN-γ and CD40L (O’Regan et al. 2000), which in turn stimulates IL-12 production from leukocytes. Together these findings suggest that OPN may play a role in polarizing early Th1 responses. More recently, OPN has also been shown to regulate IFN-γ and IL-17 production by T cells in an αvβ3-dependent manner and to dampen IL-10 in a CD44-dependent manner (Murugaiyan et al. 2008). This appears to be important for the progression of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. The same authors found that during EAE, OPN expression was elevated in DCs both in the periphery and in the CNS (Murugaiyan et al. 2008). This correlated with the increased expression of OPN in DCs and increased expression of OPN receptors CD44 and αvβ3 on T cells isolated from patients affected by multiple sclerosis (Murugaiyan et al. 2008). These results may indicate that OPN produced by DCs in EAE is linked to the production of IL-17 (Murugaiyan et al. 2008; Shinohara et al. 2008b). Recent studies indicate that OPN enhances the survival of autoreactive T cells in a NF-κB- dependent manner. Enhanced OPN-induced T cell survival also appears to promote progression of EAE (Hur et al. 2007). In addition, an anti-OPN antibody has been shown to promote apoptosis of activated T cells, particularly CD4+ T cells, by inhibiting activation of NF-κB and by altering the balance between the proapoptotic proteins, Bim and Bax, and the antiapoptotic protein, Bcl-2, in a model of rheumatoid arthritis (Fan et al. 2008). Finally, a subset of lymphocytes bridging innate and adaptive immunity called invariant natural killer T (iNKT) cells has also been shown to be regulated by OPN. Diao et al. found that the number of peripheral iNKT cells was significantly reduced in OPN-deficient mice compared with wild-type mice. This appeared to be consequence of impairment of intrathymic iNKT cell maturation and significant alteration of iNKT cell function as well (Diao et al. 2004). Dendritic cells OPN plays a key role in DC maturation, migration, and polarization. Interestingly, immature IL-4 and GM-CSF differentiated DCs express high levels of OPN, and OPN production decreases when DCs are stimulated with LPS and CD40L (Kawamura et al. 2005; Schulz et al. 2008). These findings suggest differential regulation of OPN in DCs and macrophages. During macrophage differentiation, OPN expression increases as monocytes adhere and differentiate into macrophages (Krause et al. 1996). In vitro OPN stimulates DC migration in a dose dependent manner in both the presence and absence of divalent cations, and studies with blocking antibodies have indicated a role for the OPN receptors αvβ3 and CD44 in S.A. Lund et al. OPN induced DC migration (Weiss et al. 2001). In vivo, DCs in OPN-null mice display a defect in DC trafficking to the lymph nodes resulting in reduced contact hypersensi- tivity responses (Weiss et al. 2001). Despite the influence of OPN on DC migratory capacity, treatment with recombi- nant OPN does not affect the expression of CCR5 and CCR7, chemokine receptors which are involved in DC migration (Schulz et al. 2008). Recently, it has also been suggested that OPN modulates different subset of DCs in the airway hypersensitivity reaction (a model of asthma). It appears that OPN increased the reaction during primary sensitization but decreased the reaction in the challenge phase, perhaps by mediating differential recruitment of different DCs (plamacytoid and conventional) subsets to the lymph nodes (Xanthou et al. 2007). OPN also influences DC cytokine production. In co- culture systems, OPN induces DC secretion of TNF-α and IL-12p70 which stimulates secretion of IFN-γ by T-cells (Renkl et al. 2005). By augmenting DC production of IL- 12, OPN can enhance Th1 polarization. As mentioned earlier, recent studies illustrate the critical role of intracellular OPN in IFN-α production by plasma- cytoid DCs, a specialized subset of DCs which produce high levels of type I interferons upon stimulation (Shinohara et al. 2006). IFN-α produced by pDCs activates NK cells, and consequently OPN deficient mice display impaired IFN-α dependent natural killer cell responses. Further, iOPN appears to decrease IL-27 in conventional DCs, leading to increases in Th17 responses (Shinohara et al. 2008b). Other biological functions of OPN Wound healing OPN is a key cytokine regulating tissue repair. OPN is present at sites of wound healing where it serves as a chemotactic molecule to recruit inflammatory cells to the site of injury. Wound healing studies in OPN-null mice have elucidated the role of OPN in tissue repair. Compared to wild type mice, incisional wounds made in OPN-null mice displayed alterations in the matrix architecture especially collagen fiber diameter, and had more residual debris (Liaw et al. 1998). Furthermore, macrophages at the wound site in OPN-null mice expressed higher levels of mannose receptor, suggesting OPN may contribute to macrophage polarization and thus regulate healing responses. Mannose receptor expression in macrophages is associated with reduced pro-inflammatory (IL-1, IL-6, IL-12, and TNF-α) cytokine secretion, upregulation of pro-healing molecules (IL-10 and TGF-β), and certain phagocytic receptors (Sica et al. 2008).