Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Due to the low degree of sequence similarity it has been speculated that murine and human S100A9 (MRP14), an inflammatory marker protein belonging to the S100 protein family, may have different cellular functions in mouse and man. The present study was undertaken to investigate the murine S100A9 protein (mS100A9) biochemically. We demonstrate that in murine peripheral CD11b+ cells up to 20% of the protein of the cytosolic fraction consists of mS100A9 and that several minor mS100A9 isoforms are present. Cell fractionation experiments with CD11b+ murine leukocytes showed that mS100A9 is found in the cytosol as well as in the insoluble fraction. Transient expression of a green fluorescence protein-mS100A9 fusion in mammalian cells revealed that mS100A9 is localized in neither the nucleus nor the vesicles. Recombinantly expressed murine S100A9 interacts in vitro with murine and human S100A8 in an in vitro glutathione S-transferase pull-down assay. Homodimerization was not observed. For further biochemical analysis the myeloid 32D cell line is presented as a suitable model, to study murine myeloid expressed S100 proteins. Both murine S100A9 and its dimerization partner mS100A8 are expressed at the onset of granulocyte-colony stimulating factor induced myeloid differentiation. Substantial amounts of this complex are constitutively secreted by granulocytic 32D cells into the medium. In summary, these data suggest, that the human and murine S100A9 may share a higher degree of functional homology than of sequence similarity.
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PMID:Biochemical characterization of the murine S100A9 (MRP14) protein suggests that it is functionally equivalent to its human counterpart despite its low degree of sequence homology. 1063 26

The hallmark of developing inflammatory lesions is the excess migration of recruited phagocytes together with the enhanced cell surface expression of adhesion molecules. Recent investigations give evidence that the two myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), which are abundant in activated or recruited phagocytes, may have a modulatory role in inflammatory responses. S100A9 displays a regulatory role in the transendothelial migration of human monocytes, and the secreted S100A8/A9 complex may serve as a transport protein to move arachidonic acid to its target cells.
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PMID:The regulatory role of MRP8 (S100A8) and MRP14 (S100A9) in the transendothelial migration of human leukocytes. 1072 90

The myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), two members of the S100 family of calcium-binding proteins, are co-expressed and form a cell-surface and cytoskeleton-associated heterodimer upon calcium mobilization which is recognized by the mAb 27E10. The heterodimer is abundantly expressed in the cytoplasm of granulocytes and a subpopulation of blood monocytes. Previously, we and others demonstrated endothelium-associated MRP8/14 in inflamed tissues in the vicinity of transmigrating leukocytes, suggesting a function of the proteins in this process. Here, we demonstrate that 27E10(+) cells represent a fast-migrating monocyte subpopulation which preferentially utilizes an ICAM-1-dependent mechanism. The following observations imply a function of MRP8/14 in the transmigration process: (i) higher secretion of MRP8/14 from 27E10(+) monocytes compared to 27E10(-) monocytes after interaction with activated endothelium, (ii) higher expression of CD11b on 27E10(+) compared to 27E10(-) monocytes, (iii) up-regulation of CD11b on 27E10(-) monocytes in the presence of MRP14 or MRP8/14 heterodimers but not MRP8 and (iv) active participation of MRP14 but not of MRP8 in transmigration as shown by blocking with respective antibodies. We show that the interaction of 27E10(+) monocytes with activated endothelium leads to MRP8/14 release which may account for the high MRP8/14 concentrations in body fluids of patients with acute or chronic inflammatory diseases. 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. Thus, MRP8/14 substantially contributes to the recruitment of monocytes to an inflammatory site.
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PMID:Transendothelial migration of 27E10+ human monocytes. 1105 79

The genomic locus of the mouse S100A9 (MRP14) gene, a myeloid expressed gene belonging to the S100 family, is split in three exons and two introns. Insertions of B1 like and LINE elements as well as several sequence repeat structures are scattered over the gene suggesting that this region of the S100 gene cluster has been the subject of a high mutational activity in mouse evolution. The insertions may represent molecular footprints of a recently postulated inversion event, which resulted in a rearrangement of the S100 gene cluster in mouse compared to man. Deletion analysis of the promoter reveals, that a 1200 bp fragment is able to direct a cell type-specific expression of a reporter gene in granulocytic 32D cells. Unexpectedly, the myeloid-specific transcription factor C/EBPepsilon is not needed for the transcriptional upregulation of the S100A9 and S100A8 genes in neutrophils. The data described here provide further insights into the evolution of the S100 gene cluster and into the myeloid-specific regulation of the murine S100A9 gene expression.
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PMID:Molecular analysis of the mouse S100A9 gene and evidence that the myeloid specific transcription factor C/EBPepsilon is not required for the regulation of the S100A9/A8 gene expression in neutrophils. 1116 45

Upon interaction with activated endothelium, monocytes and neutrophils form complexes of myeloid-related protein 8 (MRP8) (S100A8) and MRP14 (S100A9), two members of the calcium-binding S100 family that are secreted during transendothelial migration. In a pilot study of 20 renal transplant recipients and a validation study of 36 renal transplant recipients, MRP8/14 serum levels were measured with an enzyme-linked immunosorbent assay for 28 d, associated with C-reactive protein and creatinine serum levels, and grouped according to biopsy-proven acute rejection. Serum levels of MRP8/14 but not C-reactive protein were significantly increased for several days during the first 2 wk for the acute rejection groups in both studies (P < 0.005, on day 6 after transplantation). As determined by using receiver operating characteristic curves, the optimal cutoff for 100% specificity and high sensitivity (67%) for acute rejection on day 6 after transplantation was calculated to be 4.2 microg/ml for MRP8/14 in the pilot study; this value was confirmed in the validation study. Positive MRP8/14 serum levels preceded acute rejection episodes by a median of 5 d. A 3-d course of intravenous methylprednisolone therapy reduced prerejection MRP8/14 serum levels from 5.7 microg/ml to 3.3 microg/ml (P < 0.05). All MRP8/14 serum levels were below the cutoff during urinary tract infections, delayed graft function, or cytomegalovirus infections, and these values did not differ significantly from control values. It is concluded that the MRP8/14 complex is a very early serum marker suitable for monitoring of acute rejection with high sensitivity and specificity.
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PMID:An increase in myeloid-related protein serum levels precedes acute renal allograft rejection. 1151 89

The S100A9 (MRP14) protein is abundantly expressed in myeloid cells and has been associated with various inflammatory diseases. The S100A9-deficient mice described here were viable, fertile, and generally of healthy appearance. The myelopoietic potential of the S100A9-null bone marrow was normal. S100A8, the heterodimerization partner of S100A9 was not detectable in peripheral blood cells, suggesting that even a deficiency in both S100A8 and S100A9 proteins was compatible with viable and mature neutrophils. Surprisingly, the invasion of S100A9-deficient leukocytes into the peritoneum and into the skin in vivo was indistinguishable from that in wild-type mice. However, stimulation of S100A9-deficient neutrophils with interleukin-8 in vitro failed to provoke an up-regulation of CD11b. Migration upon a chemotactic stimulus through an endothelial monolayer was markedly diminished in S100A9-deficient neutrophils. Attenuated chemokinesis of the S100A9-deficient neutrophils was observed by using a three-dimensional collagen matrix migration assay. The altered migratory behavior was associated with a microfilament system that was highly polarized in unstimulated S100A9-deficient neutrophils. Our data suggest that loss of the calcium-binding S100A9 protein reduces the responsiveness of the neutrophils upon chemoattractant stimuli at least in vitro. Alternative pathways for neutrophil emigration may be responsible for the lack of any effect in the two in vivo models we have investigated so far.
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PMID:Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. 1252 7

Neutrophils are rapidly recruited to sites of inflammation and are thereby at the forefront of the organism's defense against numerous attacks. As unspecific phagocytes, they belong to the so-called innate immunity. Two S100 proteins, namely S100A9 (MRP14) and S100A8 (MRP8), constitute roughly 40% of the cytosolic protein in these cells, implying by their pure abundance an important role in the effector functions of neutrophils. However, despite intense research in the past 15 years, the puzzle that may embed both molecules into the neutrophil/monocyte physiology is still incomplete. One reason might be the conformational variability the S100A9 and S100A8 molecules can adopt. They readily form hetero- and homodimeric, trimeric as well as tetrameric complexes, but they evidently do also exert specific functions as monomers. An ever-increasing body of information suggests that S100A9 plays a prominent role in leukocyte trafficking and arachidonic acid metabolism. In addition, elevated levels of S100A9 and S100A8 in body fluids of inflamed tissues strengthen the view that these molecules are important players in fighting inflammation. The aim of this review is to give an update on the current developments concerning the S100A9/S100A8 molecule in biology and medicine.
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PMID:S100A9/S100A8: Myeloid representatives of the S100 protein family as prominent players in innate immunity. 1264 5

Lentigo maligna (LM), a type of malignant melanoma in situ, and pigmented actinic keratosis (PAK) may have similar clinical appearances but are different in prognosis and treatment. Diagnosis is established by skin biopsy. In certain cases, microscopic features may be very similar in both entities, making it difficult to determine whether the pigmented atypical cells are keratinocytes or melanocytes. Immunohistochemical markers can be useful for the identification of melanocytes in these cases. There are limitations to the use of some standard immunohistochemistry markers, however. S100 proteins are a varied group of proteins that are of special interest because of their dysregulated expression in neoplastic disorders. Their expression is changed during malignant transformation, progression, and/or metastasis in various cell lines and tumors, including melanomas. Our study analyzed the expression of several of the S100 protein subtypes (S100A2, S100A6, and S100A8/A9 or A12) in 38 LM cases and 44 PAK cases to define their potential value in the distinction between these entities together with their role in the development of early malignant melanoma of the skin. The results showed an upregulation of S100A2 protein in atypical keratinocytes in PAK and in normal keratinocytes adjacent to melanoma cells in LM. There was also an upregulation of S100A8/A9 or A12 protein, as detected by the antibody MAC387, in normal keratinocytes adjacent to both atypical keratinocytes and melanocytes in PAK and LM, respectively. There were statistically significant differences in the level of positive cells and in the pattern of immunoreactivity for anti-S100A2 and MAC387 in each entity, however. Moreover, the findings of our study support the notion that melanocyte-keratinocyte interactions are abnormal in both of these disease entities and may be involved in their progression.
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PMID:S100A protein expression in the distinction between lentigo maligna and pigmented actinic keratosis. 1265 89

Macrophages are decisive cells for the course of leprosy as they phagocytose Mycobacterium leprae and have the potential to influence the specific immune response. Expression and release of the myeloid-related protein (MRP) 8 and MRP14 (S100A8 and S100A9) characterize a proinflammatory subtype of macrophage that is prominent in, for example, murine infection with lack of a T helper 1 cell response and in certain highly active chronic inflammations of mice and humans. We investigated cutaneous biopsies of the different forms of leprosy (41 untreated patients) including leprosy reaction type 1 (reversal reaction) and type 2 (erythema nodosum leprosum) (n = 18) for expression of MRP8 and MRP14 by subtypes of macrophages. Concomitantly we determined serum levels of MRP8 and MRP14 by sandwich enzyme-linked immunosorbent assay. Expression of MRP8 and MRP14 by CD68-positive macrophages was low in tuberculoid leprosy and rose significantly in borderline tuberculoid leprosy and especially in multibacillary forms, there being expressed by mycobacteria-loaded foam cells. A significant rise of MRP8 and MRP14 expression also occurred in lepra reactions compared to the corresponding non-reactional forms. In type 2 reactions this additional increase was associated with a significant elevation of serum levels. In type 1 it was associated with expression of MRP8 and MRP14 by epitheloid and giant cells, which so far were considered not to express both proteins. In conclusion, we present evidence that the two prominent proteins MRP8 and MRP14 can be re-expressed in vivo by tissue macrophages in chronic infection, that their increased expression is characteristic for a macrophage subtype associated with high inflammatory but low antimycobacterial activity in the absence of a T helper 1 response, and that their significant rise in serum during erythema nodosum leprosum bears diagnostic and pathophysiological relevance.
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PMID:High expression of myeloid-related proteins 8 and 14 characterizes an inflammatorily active but ineffective response of macrophages during leprosy. 1505 85

New experimental approaches of molecular medicine such as transcriptome and proteome analysis have been implemented in rheumatology research. Two-dimensional gel electrophoresis in combination with mass spectrometry was used to visualize and to identify proteins in synovial fluid (SF) and plasma samples from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The small calcium binding protein S100A9 (MRP14) was identified as a discriminatory marker protein in SF by global proteomic analysis. 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. 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. Initial studies on RA patients also indicate that plasma levels of the S100A8/A9 heterocomplex are a useful marker in monitoring anti TNFalpha therapy.
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PMID:Proteome analysis reveals disease-associated marker proteins to differentiate RA patients from other inflammatory joint diseases with the potential to monitor anti-TNFalpha therapy. 1523 25


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