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Using surface plasmon resonance (SPR) analysis recombinant HMGB1 was shown to bind TLR4:LY96(MD2) in a concentration-dependent manner (Yang H et al. 2010; Yang H et al. 2015). The binding required cysteine at the position 106 whereas the C106A HMGB1 mutant failed to bind TLR4:LY96 (Yang H et al. 2010). In addition, C106A and C106S HMGB1 failed to stimulate TNF release in mouse peritoneal macrophages (Yang H et al. 2010). The activity of HMGB1 was found to depend on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3-) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012). Biosensor-based SPR analysis confirmed that only the disulfide bond (C23-S-S-C45)-containing HMGB1 binds to LY96 (MD2) with high affinity (apparent Kd = 12 nM) regardless of whether LY96 or HMGB1 was immobilized on the sensor chip (Yang H et al. 2015). Moreover, TLR4 and LY96 (MD2) were recruited into CD14-containing lipid rafts of mouse RAW264.7 macrophages after stimulation with HMGB1, suggesting that an optimal HMGB1-dependent TLR4 activation in vitro required the co-receptor CD14 (Kim S et al. 2013). In addition to stimulating cells by direct interaction with innate immune receptors, HMGB1 was found to form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) (Youn JH et al. 2008; Wahamaa H et al. 2011; Hreggvidsdottir HS et al. 2009) HMGB1 in complex with LPS, IL1alpha or IL1beta boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wahamaa H et al. 2011; He ZW et al. 2013). HMGB1 was reported to associate and amplify the activity of LPS (TLR4 ligand), CpG-ODN (TLR9 ligand) or Pam3CSK4 (TLR1:TLR2 ligand) in a synergistic manner when added to the cultures of human peripheral blood mononuclear cell (PBMC) (Hreggvidsdottir HS et al. 2009).
S100A1 is a Ca(2+)-sensing protein of the EF-hand family. S100A1 is expressed predominantly in cardiomyocytes, where it regulates Ca(2+)-dependent signaling events (Wright NT et al. 2005; Cannon BR et al. 2011; Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014; Ritterhoff J & Most P 2012). In response to ischemic/hypoxic damage of cardiomyocytes, S100A1 is released or transferred to the extracellular region through open channels on membrane (Rohde D et al. 2014). The extracellular S100A1 activates signal and promotes cell survival pathways, including inflammation response via Toll-like receptor 4 (TLR4) (Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014). In rodent H9C2 cells S100A1 was found to regulate the inflammatory response and oxidative stress via TLR4/ROS/NFkappaB pathway ( Yu J et al. 2015).
S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 tend to form homodimers and heterodimers (Kumar RK et al. 2001; Riva M et al. 2013; Korndorfer IP et al. 2007). The heterodimeric S100A8:S100A9 complex is termed calprotectin and is considered as the predominantly occurring form. In response to stress S100A8:S100A9 is primarily released from activated or necrotic neutrophils to extracellular milieu where it functions as an innate immune mediator of infection, autoimmunity, and cancer (Ehrchen JM et al. 2009; Rammes A et al. 1997; Frosch M et al. 2000; Loser K et al. 2010).
S100A8 and S100A9 protein levels were elevated in patients with a wide range of inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, acute lung inflammation, sepsis and vasculitis (Ehrchen JM et al. 2009; van Zoelen MA et al. 2009; Vogl T et a;. 2012; Holzinger D et al. 2012; Rahman MT et al. 2014; Anink J et al. 2015. Increased S100A8 and S100A9 serum levels have been also identified as independent risk predictors for various cardiovascular diseases such as acute coronary syndrome and myocardial infarction (Yonekawa K et al. 2011; Cotoi OS et al. 2014; Larsen SB et al. 2015).
SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD2 in a Ca2+ -dependent manner, with involvement of the CRD region (Yamada et al. 2006; Yamazoe M et al. 2008). SP-A was also shown to interact with CD14 (Sano H. et al. 1999). Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection together with functional characterization of cell surface receptors revealed both pro- and anti-inflammatory functions of SP-A and SP-D in the control of lung inflammation in mammals (Guillot L et al. 2002; Madan T et al. 2001, 2005, 2010; Wang JY & Reid KB 2007; Yamada et al. 2006; Yamazoe M et al. 2008; Wang G et al. 2010). Anti-inflammatory effects of SP-A caused inhibition of NF-kB activation and accumulation of inhibitory protein I kappa B-alpha (IkB-alpha) in LPS-challenged alveolar macrophages (AM) (Wu Y et al. 2004). SP-A also inhibited tumor necrosis factor-alpha (TNFalpha) expression induced by smooth LPS but not by rough LPS in the human macrophage-like cell line U937 cells (Sano H. et al. 1999). In addition, SP-A attenuated cell surface binding of smooth LPS and subsequent NF-kB activation in TLR4/MD2 expressing human embryonic kidney (HEK293) cells (Yamada et al. 2006). Like SP-A, SP-D bound to complex of sTLR4:MD2 was found to down regulate a secretion of TNFalpha and activation of NF-kB in LPS-stimulated AM and TLR4/MD-2-transfected HEK293 cells (Yamazoe M et al. 2008). SP-A and SP-D are thought to prevent LPS-elicited inflammatory responses by altering LPS binding to its receptors, TLR4:MD2 or CD14 (Sano H. et al. 1999; Yamada et al. 2006; Yamazoe M et al. 2008).