2, 3 Extracellular matrix (ECM) proteins can act as inflammatory stimuli by promoting leukocyte migration and by inducing the expression of proinflammatory cytokines and growth factors.4 These ECM molecules are considered endogenous danger signals, or damage-associated molecular patterns (DAMPs).5 Tenascin-C (Tnc) is likely a prominent DAMP molecule within the ECM.6 Tnc is a hexameric protein of 1.5 million Da consisting of a single fibrinogen-like domain (FBG)

and multiple fibronectin (FN)-type III and epidermal growth factor (EGF)-like domains.7 Tnc is often called an oncofetal molecule because of its unique expression8; Trichostatin A it is abundantly expressed during embryogenesis, and is not normally expressed in adult tissues, with the exception of specific hematopoietic and lymphoid tissues.9 Notably, Tnc emerges in adult tissues during conditions

associated with high rates of cell turnover and migration, including wound repair, tumorigenesis, rheumatoid arthritis, multiple sclerosis, Metformin research buy and hepatitis.5, 7, 10, 11 The action of Tnc is complex; it is accepted that Tnc is involved in cell-cell interactions, cell-adhesion, and deadhesion events.12 Tnc can influence cell behavior through interactions with cell surface receptors and by altering cell binding to other ECM proteins.13 Leukocytes can form low-avidity adhesions to Tnc, producing tethering and rolling under flow in a more efficient manner than on selectins.14 Although in vitro assays have supported a role for Tnc in leukocyte migration and activation, its precise function at sites of tissue injury remains mostly unclear. It has been recently demonstrated that Tnc

induces cytokine release and tissue destruction in arthritic joint disease.6 The role of Tnc at sites of inflammation is defined by the type of tissue injury or by the participating cell types.13 In the present study, we used Tnc−/− mice to examine the significance of Tnc expression in hepatic IRI. ALT, alanine transaminase; AST, aspartate transaminase; DAMP, damage-associated molecular pattern; ECM, extracellular matrix protein; EGF, epidermal growth factor; FBG, fibrinogen-like domain; ICAM-1, intercellular adhesion molecule; IRI, ischemia/reperfusion injury; Mac-1, mouse macrophage MCE公司 antigen-1; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; OLT, orthotopic liver transplantation; PCNA, proliferation cell nuclear antigen; PECAM-1, platelet endothelial cell adhesion molecule-1; TLR4, Toll-like receptor 4; Tnc, tenascin-C; VCAM-1, vascular cell adhesion molecule-1. Tnc-deficient (Tnc−/−) knockout (KO) mice (C57BL/6N-TgH) were obtained from Riken, Japan.15 Toll-like receptor 4-deficient (TLR4−/−) mice (C57Bl/10ScNJ-Tlr4) and C57Bl/10J controls (wildtype, WT) were purchased from the Jackson Laboratory.