The Ca2+-binding Proteins S100A8 and S100A9 Are Encoded by Novel Injury-regulated Genes

Abstract

To gain insight into the molecular mechanisms underlying cutaneous wound repair, we performed a large scale screen to identify novel injury-regulated genes. Here we show a strong up-regulation of the RNA and protein levels of the two Ca 2؉ -binding proteins S100A8 and S100A9 in the hyperthickened epidermis of acute murine and human wounds and of human ulcers. Furthermore, both genes were expressed by inflammatory cells in the wound. The increased expression of S100A8 and S100A9 in wound keratinocytes is most likely related to the activated state of the keratinocytes and not secondary to the inflammation of the skin, since we also found up-regulation of S100A8 and S100A9 in the epidermis of activin-overexpressing mice, which develop a hyperproliferative and abnormally differentiated epidermis in the absence of inflammation. Furthermore, S100A8 and S100A9 expression was found to be associated with partially differentiated keratinocytes in vitro. Using confocal microscopy, both proteins were shown to be at least partially associated with the keratin cytoskeleton. In addition, cultured keratinocytes efficiently secreted the S100A8/A9 dimer. These results together with previously published data suggest that S100A8 and S100A9 are novel players in wound repair, where they might be involved in the reorganization of the keratin cytoskeleton in the wounded epidermis, in the chemoattraction of inflammatory cells, and/or in the defense against microorganisms.After cutaneous injury, a series of biological events takes place that aims at the reconstruction of the damaged skin. Among them are the migration, proliferation, and differentiation of inflammatory, epithelial, and mesenchymal cells. These cells exert specific functions in a temporally and spatially coordinated manner such as the removal of irreversibly destructed tissue, the deposition of new extracellular matrix, and the reestablishment of the cutaneous barrier (1, 2). These processes are well described at the histological level, but little is known about their molecular basis.To gain insight into the molecular mechanisms that underlie the repair process, we performed a large scale subtractive hybridization screen to systematically identify genes that are differentially expressed in injured compared with normal skin. To minimize the risk of detecting differences in gene expression levels due to changes in cellular composition rather than to transcriptional regulation, we compared normal skin with early (24 h) wounds, because only minor changes in cell type composition occur during the initial wound healing period.One of the cDNA clones that we obtained encodes the murine S100A8 protein (also known as calgranulin A, MRP8, leukocyte protein L1, or cytokine CP-10). S100 proteins are intracellular Ca 2ϩ -binding and Ca 2ϩ -modulated proteins that form antiparallel noncovalently linked dimers in solution and play a role in various Ca 2ϩ -mediated cellular functions including cell growth and differentiation, energy metabolism, cytoskeletalmembrane interactions; some of th...

Expression of Calcium-Binding Proteins MRP8 and MRP14 in Inflammatory Muscle Diseases

“…Although it is not possible to determine the exact concentrations of MRP8 and MRP14 at the local sites of destruction of myofibers in IM, MRP8/MRP14 concentrations used in our in vitro assays are not higher than those demonstrated in various inflammatory exudates in vivo such as wound secretions and synovial fluid of rheumatoid arthritis. 16,49 The detection of such large amounts of MRP8/MRP14 in certain inflammatory conditions thus indicates that our in vitro data bear relevance in vivo.…”

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

“…However, deregulated expression of several members of the S100 family, including S100A8 and S100A9, under various pathologic conditions has been reported (7,35). Besides the well-documented expression in inflammatory skin diseases (15), S100A8 and S100A9 and other members of the S100 family recently have been associated with rheumatoid arthritis (36), psoriasis (37), cutaneous wound repair (16), and various experimental and human neoplasms (4, 17 -19). It is noteworthy that the patterns of differential gene expression in cancer, particularly in prostate and liver cancer, strongly correlate with the pattern of differential gene expression during wound-healing processes (38).…”

“…The proteins were suggested to form S100A8/S100A9 heterocomplexes (12,13), which were shown to be secreted by activated monocytes (14). Expression of S100A8 and S100A9 in epithelial tissues was first described in context with squamous epithelia, e.g., various inflammatory skin diseases (15), and with murine and human wound repair (16). More recently, an association of S100 protein expression with adenocarcinomas in humans has emerged.…”

L’expression génique dans le cortex cérébral de rats anémiques aigus: une analyse par microarray

“…29,30 Finally, our microarray data showed a significant up-regulation of S100A9, a marker of organ injury at 6 and 24 hr. 31,32 However, this pro-inflammatory molecule did not increase to the same degree as the Anesthesia Control at 24 hr. Clearly, further detailed investigations are required to better understand the roles of numerous genes with novel and complex expression patterns in the cerebral cortex following acute hemodilution.…”