Disease relevance of S100A8

• S100A8 and S100A9 in human arterial wall. Implications for atherogenesis [1].
• S100A9 but not S100A8 was found in macrophages in ApoE-/- murine atherosclerotic lesions, whereas both proteins are expressed in human giant cell arteritis [1].
• Persistent elevation of S100A8/A9 after IVIG was found in patients who later developed coronary aneurysms [2].
• It was found that plasma levels of the S100A8/A9 heterocomplex correlate well with levels in SF, and hence, determination of plasma levels can be used to distinguish RA patients from patients with other inflammatory joint diseases, as well as from OA patients and controls [3].
• Increased serum levels of the S100A8 (MRP-8) protein have been reported in inflammatory conditions including bacterial infection, arthritis, and cystic fibrosis (CF) [4].
• Our study provides an extensive analysis of S100A8 and S100A9 in pancreatic disease and highlights a potentially important relationship between pancreatic cancer cells and their surrounding microenvironment [5].

High impact information on S100A8

• Leukocyte L1 protein and the cystic fibrosis antigen [6].
• However, a serum protein abnormality present in unaffected heterozygotes as well as in affected homozygotes has been described, and immunological quantitation of this protein, termed cystic fibrosis antigen, allows the three genotypes to be distinguished [7].
• Somatic cell hybrids between the mouse myeloid stem-cell line WEHI-TG and myeloid leukaemia cells express cystic fibrosis antigen only when human chromosome I is present [7].
• HIF1{alpha} delays premature senescence through the activation of MIF [8].
• These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction [9].

Chemical compound and disease context of S100A8

• We previously reported that S100A8/A9 induces apoptosis of EL-4 lymphoma cells via the uptake of extracellular zinc in a manner similar to DTPA, a membrane-impermeable zinc chelator [10].
• CONCLUSIONS: The 14 amino acid peptide from S100A8 impairs the catabolism of glucose by myoblasts in vitro and may cause hyperglycemia in vivo [11].
• Effects of EB and P on myeloperoxidase activity and MIF concentration were also assessed at 7 days in dextran sulfate sodium-induced colitis [12].
• We investigated whether estradiol and progesterone influence MIF, IL-1beta, and TNF-alpha production in experimental colitis [12].
• Macrophage migration inhibitory factor (MIF), a target of sex steroids in other inflammatory models, promotes interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha release in colitis [12].

Biological context of S100A8

• Murine S100A8 is regulated by inflammatory mediators and recruits macrophages with a proatherogenic phenotype [1].
• S100A8 and S100A9, the Ca2+-binding neutrophil cytosolic proteins, are associated with innate immunity and regulate processes leading to leukocyte adhesion and transmigration [1].
• In this study, we report that S100A8, S100A9, and S100A8/A9 caused neutrophil chemotaxis at concentrations of 10(-12)-10(-9) M [13].
• In view of the unusual abundance in neutrophilic cytosol (approximately 40% of cytosolic protein) our findings assign an important role for S100A8/A9 as mediator between calcium signaling and arachidonic acid effects [14].
• Gene expression analyses in immune system cells supported these findings and indicated that bacterial activation of neutrophils caused upregulation of S100A8, S100A9, and S100A13 [15].

Anatomical context of S100A8

• BACKGROUND: Calprotectin (complex of S100A8 and S100A9) is the major calcium and zinc-binding protein of phagocytes [16].
• Further investigations have to explore the exact function of the S100A8/A9-arachidonic acid complex both inside and outside of neutrophils [14].
• These results indicate that the effects of IVIG in KD may be mediated by suppression of an array of immune activation genes in monocytes, including those activating FcgammaRs and the S100A8/A9 heterocomplex [2].
• Stimulation of neutrophil-like HL-60 cells with phorbol 12-myristate 13-acetate led to the secretion of S100A8/A9 protein complex, which carried the released arachidonic acid [14].
• Here we demonstrate S100A8 and S100A9 protein and mRNA in macrophages, foam cells, and neovessels in human atheroma [1].

Associations of S100A8 with chemical compounds

• When elevation of intracellular calcium level was induced by A23187, release of arachidonic acid occurred without secretion of S100A8/A9 [14].
• Neutrophil preincubation with the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine and the Syk tyrosine kinase inhibitor trans-3,3',4,5'-tetrahydrozystilbene significantly reduced the release of S100A8/A9, suggesting that the Src tyrosine kinase family and Syk were involved [17].
• Recombinantly expressed murine S100A9 interacts in vitro with murine and human S100A8 in an in vitro glutathione S-transferase pull-down assay [18].
• Results: Norepinephrine stimulated the expression of S100A8/S100A9 mRNAs via beta-adrenergic receptors in U-937 cells and significantly increased calprotectin production to about 3.6-fold that of the control [19].
• S100A8 and S100A9 calcium-binding proteins: localization within normal and cyclosporin A-induced overgrowth gingiva [20].

Physical interactions of S100A8

• The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries [21].
• S100A8/A9 complexes, as well as S100A9 homodimers, stimulated the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages [22].
• Interaction of S100A8/S100A9-arachidonic acid complexes with the scavenger receptor CD36 may facilitate fatty acid uptake by endothelial cells [23].
• The CF-antigen has been shown to consist of the two calcium-binding proteins MRP8 and MRP14 [24].
• MIF appears to interact with cell surface CD74, with consequent activation of MAP kinases but possibly not NFkappaB intracellular signal transduction [25].

Regulatory relationships of S100A8

• CONCLUSION: These data suggest that MIF may regulate RA synovial hyperplasia by acting directly and via involvement in the effects of IL-1 beta and TNFalpha [26].
• By contrast, MIF induced phosphorylation of extracellular signal-regulated kinase (ERK) MAP kinase [26].

Other interactions of S100A8

• Plasma S100A8/A9 heterocomplex, but not S100A9, levels were elevated in patients with acute KD compared with those in febrile controls [2].
• We previously identified a carboxylate modification of N-linked glycans that is recognized by S100A8, S100A9, and S100A12 [27].
• Conclusions.-The S100A8 and S100A12 proteins are considered markers of non-infectious inflammatory disease, while the function of S100P is still largely unknown [28].
• Isolated ST cells from patients with RA spontaneously released larger amounts of S100A8/A9 protein than did the cells from patients with OA [22].
• Released MRP8/14 may serve a function by enhancing CD11b expression and/or affinity in human monocytes and by participating in the transendothelial migration mechanism [29].
• Repression of annexin A6 expression by small interfering RNA in SKBR3 cells abolishes the cell surface exposition of S100A8/A9 upon calcium influx, suggesting that annexin A6 contributes to the calcium-dependent cell surface exposition of the membrane associated-S100A8/A9 complex [30].

Analytical, diagnostic and therapeutic context of S100A8

• Expression of surfactant protein-C, S100A8, S100A9, and B cell markers in renal allografts: investigation of the prognostic value [31].
• Furthermore, an additional protein, identified by matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) as S100A8, exhibited an increased expression in the same specimens of malignant tissues as the S100A9 protein [32].
• Employing site-directed mutagenesis we found that distinct hydrophobic amino acids of helix I/I' are located at a crucial site of the S100A8/S100A9 dimer interface, whereas conserved residues within helix IV/IV' are not important for heterodimerization [33].
• The expression of S100A8/S100A9 mRNAs was examined by northern blotting and the amount of calprotectin was measured by enzyme-linked immunosorbent assay (ELISA) [19].
• To confirm these results and to examine the reproducibility and the applicability as a diagnostic marker, levels of the S100A8 (MRP8)/A9 (MRP14) heterocomplex in plasma and in synovial fluid were validated from patients with RA, OA, and other inflammatory joint diseases using enzyme immunoassay techniques [3].

References