S100A8 (also known as MRP8) and S100A9 (MRP14) are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer (Ehrchen JM et al. 2009; De Jong HK et al. 2015). S100A8 & S100A9 have been identified as important damage-associated molecular patterns (DAMPs) recognized by TLR4 (Foell D et al. 2007; Vogl t et al. 2007; 2012; Kang JH et al. 2015). Surface plasmon resonance studies showed that S100A8 can directly interact with TLR4:MD2 complex with Kd of 1.1-2.5 x 10e-8 M ((Vogl T et al. 2007). Human embryonic kidney cells stably transfected with TLR4,CD14 and MD2 demonstrated a strong induction of proinflammatory cytokines like TNFalpha and IL8 after stimulation with LPS as well as with S100A8 (Vogl T et al. 2007). Induction of NFkB responses by S100A9 in human monocytic THP-1 cell line and mouse bone marrow-derived dendritic cells was TLR4-dependent (Riva M et al. 2012). Moreover, induction of MUC5AC mRNA and protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells occurred in a dose-dependent manner trough TLR4 signaling pathway (Kang JH et al. 2015). In addition, S100A8:S100A9 was reported to regulate cell survival of human neutrophils through a signaling mechanism involving an activation of MEK:ERK1 via TLR4 (Atallah M et al. 2012). In experimental mouse models the proinflammatory and TLR4-dependent activities of S100A8:S100AA9 were further confirmed (Vogl t et al. 2007; Loser K et al. 2010; Kuipers MT et al. 2013; Deguchi A 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).