However, the liver was different from skin, gut, and brain in that integrins were often not involved and other

adhesion molecules were implicated. Indeed, anti-adhesion was demonstrated for VAP-1 in hepatic sinusoids in a model of hepatitis.[9] Adhesion molecules such as CD44/hyaluronic acid and Siglec-10/VAP-1 have also been implicated in interactions between leukocytes Inhibitor Library and endothelium in liver.[33-36] McDonald et al.[33] have shown that CD44 was responsible for reversible neutrophil adhesion to hyaluronic acid (HA) within liver sinusoids in vivo and the disruption of CD44-HA interactions reduced liver injury in response to bacterial lipopolysaccharides. The CD44-dependent adhesion was reversible and not replaced by other adhesive mechanisms or physical trapping, suggesting a key role for molecular adhesion in liver sinusoids.[33] Moreover, Siglec-10, a member of the family of sialic acid-binding Ig-like lectins (Siglecs), was first identified as

a leukocyte surface ligand and a substrate for VAP-1, which is important Ganetespib order in lymphocyte recruitment in liver.[35, 36] These findings are crucial for the development of new antiinflammatory therapy rather than traditional anti-integrin therapy. Herein, we provide further evidence that VAP-1 is a good target to ameliorate the autoimmune-induced hepatic injury by selectively regulating recruitment of CD4 Th2 but not Th1 lymphocytes. We analyzed the effect of anti-VAP-1 therapy for lymphocyte recruitment to the liver using a well-established Con A-induced hepatitis model.[4, 5, 7, 8] Con A treatment caused acute liver injury as assessed by increased serum transaminase level as early as 4 hours (data not shown) after intravenous administration and continued until 24 hours. Con A treatment is not specific for liver and causes injury elsewhere, including lung, where many neutrophils are recruited but anti-VAP-1 was ineffective (Supporting Fig. 4), indicating that VAP-1 does not affect neutrophil recruitment Histone demethylase in lung or as previously reported

in liver.[9] VAP-1 functions as both an adhesion molecule and a generator of oxidants. Our data demonstrate that blocking a specific adhesion molecule holds some therapeutic promise, while inhibitors of the mono-oxidase activity showed marginal (25%) benefit. However, inhibiting both functions of VAP-1 reduced Con A-induced inflammation to the greatest extent, suggesting that targeting both functions of VAP-1 could have optimal benefit. The attenuated liver injury in anti-VAP-1-treated mice and VAP-1-deficient mice correlated with reduced CD4+ T cell recruitment and reduced numbers of IL-4 producing T cells. This is in line with the essential role of CD4+ T cells in induction of liver injury derived by Con A but our data point toward a Th2 subset.