, 2001), gingival fibroblasts and T cells (Belibasakis et al., 2010), which are crucial for the induction of cytokine responses and the establishment of chronic inflammation in periodontitis (Holzhausen et al., 2010; Fagundes et al., 2011). Gingipains can also stimulate IL-6 production by oral

epithelial cells Pritelivir order (Lourbakos et al., 2001) and IL-8 production by gingival fibroblasts (Oido-Mori et al., 2001), enhancing the inflammatory responses. However, they can also proteolytically inactivate both anti-inflammatory (IL-4, IL-5) and pro-inflammatory (IL-12, IFN-γ) cytokines (Yun et al., 1999, 2001, 2002; Tam et al., 2009). A number of particularly interesting effects are exerted by the gingipains on components of the complement system. Arg-X gingipains can cleave the C5 molecule, resulting in release of its C5a component, which is crucial for enhancing C646 cost the recruitment of PMNs (Wingrove et al., 1992; Imamura et al., 2001). On the other hand, Lys-X can inactivate the C5a receptor on PMNs, an action that may actually impair their recruitment (Jagels et al., 1996a, b). Along this line, the Arg-X gingipains can degrade the C3 molecule, potentially contributing to decreased bacterial opsonization (Schenkein et al., 1995). This property could confer increased resistance of P. gingivalis to bactericidal activity. Apart from their effect on immune responses, gingipains may

also be involved in the binding of P. gingivalis to host cells, as Rgp–Kgp complexes have been shown to mediate adherence on gingival epithelial cells and gingival fibroblasts (Chen et al., 2001; Grenier et al., 2003; Andrian et al., 2004). Interestingly, when P. gingivalis intracellularly invades Montelukast Sodium gingival epithelial cells, expression of gingipain is downregulated (Xia et al., 2007). Gingipains may also affect vascular permeability and bleeding at the periodontal site. They can proteolytically activate plasma kallikrein and bradykinin, or alternatively increase the release of thrombin and prothrombin,

which can result in increased vascular permeability and PMN influx (Imamura et al., 1994, 1995a). Moreover, by degrading fibrinogen (Scott et al., 1993), they may contribute to inhibition of blood coagulation and increase bleeding at the site (Imamura et al., 1995a) , thus enhancing the availability of hemin required for P. gingivalis growth. Collectively, studies in various experimental systems indicate that gingipains have seemingly contradicting actions on the innate immune responses, hampering interpretation of their role in the pathogenesis of periodontitis. Nevertheless, such differences may be reconciled by the existence of a concentration gradient of gingipains in the tissue (Pathirana et al., 2010). Closer to the gingival epithelial barrier where the biofilm resides, gingipain concentrations are high, causing degradation or deregulation of various components of the immune response.