41,42 It therefore seems likely that modest increases in CXCR2 ligands may promote liver regeneration, while massive increments can be hepatotoxic. This concept has been further supported by in vitro studies which describe LY2109761 low dose MIP-2 pre-treatment was hepatoprotective
against hypoxia-reoxygenation injury, whilst hepatocytoxicity was observed with higher concentrations.39 An exactly analogous situation is observed with TNF, which is a hepatoprotective, pro-proliferative pathway of ischemic preconditioning, yet a key mediator of liver injury after IR in naïve livers.43 Toll-like receptors (TLRs) are trans-membrane proteins which form the major pattern recognition receptors that transduce signals in response to diverse pathogen-associated
molecular patterns (PAMPs).44 TLRs are ubiquitous. Their expression rapidly changes after exposure to triggers such as pathogens, cytokines and environmental stressors.44,45 PAMPs consist of lipids, lipoproteins, proteins and/or nucleic acids. Each TLR recognizes distinct PAMPs and their activation initiates innate and adaptive responses via cytokines, interferons, chemokines and their associated receptors.44–46 TLR activation also increases effector functions, such as phagocytosis, and enhances the capacity of T cell antigen presentation. www.selleckchem.com/products/VX-809.html Moreover, TLRs can recognize degradation products of host-derived molecules, called damage-associated molecular patterns (DAMPs); the latter includes extracellular matrix components such as heparan sulphate, hyaluronan fragments and fibronectin.47–49 There is growing evidence that TLRs in the liver, expressed on hepatocytes, Kupffer cells (KCs) as well as neutrophils, play an important role in the activation of immune cells in IR injury, and in mediating hepatocyte damage (Table 1).44,50 TLR signals emanate from either MCE公司 the cell surface (TLR1, TLR2, TLR4, TLR5, TLR6), or from the endolysosomal compartment (TLR3, TLR7, TLR9).44,46 Upon ligation, they undergo
conformational change and recruit cytoplasmic adaptor proteins via a Toll/Il-1 receptor (TIR) domain. The proximal adaptor proteins that mediate TLR signalling are myeloid-differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (also known as Toll/Il-1 receptor adaptor-like protein, TIRAP), TIR domain-containing adaptor protein inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM). TIRAP and MyD88 mediate signals from TLR3, and together with TRAM, also from TLR4. Downstream of MyD88, regulatory kinases are recruited, leading to activation of NF-κB and mitogen activated protein kinase (MAPK) pathways. Type 1 interferons are activated downstream of TRIF. TLR4 is the only TLR that can activate both TIRAP-MyD88 and the TRAM-TRIF pathways. MyD88 is associated with all TLR types except TLR3 (Fig. 2).45,46 Its signalling via TLR2 and TLR4 requires TIRAP.