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

Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation. Tazarotene (AGN 190168), a retinoic acid receptor (RAR)-specific retinoid, is effective in the treatment of psoriasis, a hyperproliferative and inflammatory skin disease. Because negative regulation of genes appears to be important in the antiproliferative and antiinflammatory action of retinoids, we studied the down-regulation of genes in skin raft cultures by this antipsoriatic retinoid. By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168. MRP-8 and SKALP are overexpressed in psoriatic lesions as compared to the normal epidermis, and they are markers of hyperproliferative keratinocyte differentiation. We also show that MRP-8 expression is retinoid inhibitable in cultured keratinocytes induced to differentiate with 10% serum or IFN-gamma, and that MRP-8 is inhibited by RAR but not by retinoid X receptor-specific retinoids in a dose-dependent manner. Finally, MRP-8, SKALP, and the previously characterized differentiation marker, transglutaminase I, are all down-regulated in vivo in psoriatic lesions after treatment with AGN 190168 in comparison to placebo. Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status.
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PMID:Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis. 895 47

The murine calcium-binding protein S100A8 is a potent chemoattractant for neutrophils and monocytes in vivo and in vitro but may also play a protective role. We show that the kinetics of induction of S100A8 mRNA in elicited murine macrophages (Mac) by LPS, IFN-gamma, and TNF were distinct from the C-C chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage-inflammatory protein-1alpha (MIP-1alpha), and RANTES. Monomeric S100A8 was predominantly secreted. IFN substantially increased S100A8 mRNA levels after 1 h with optimal induction after 12 h; induction by TNF was slower and more sustained. TNF did not up-regulate MCP-1 and MIP-1alpha mRNA in these cells. Luciferase reporter assays confirmed that LPS and IFN induce S100A8 gene transcription and mRNA in LPS-treated Mac showed little decay over 16 h, whereas transcripts induced by IFN and TNF were markedly less stable. Newly synthesized proteins may be required for mRNA transcription and stabilization in response to LPS. S100A9 associates with A8 in neutrophils, but was not coinduced with S100A8. S100A8 gene induction in Mac stimulated with LPS and IFN may be modulated by mobilization of intracellular Ca2+ concentration from distinct intracellular stores and/or the extracellular compartment and by distinct pathways involving protein kinase C and leading to activation of mitogen-activated protein kinase.
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PMID:IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8. 1077 2

The murine calcium binding protein S100A8 (A8) is a leukocyte chemoattractant, but high levels may be protective and scavenge hypochlorite. A8 is induced by LPS, IFN-gamma, and TNF in elicited macrophages. Th2 cytokines generally suppress proinflammatory gene expression, and IL-4 and IL-13 partially decreased A8 induction in macrophages and endothelial cells stimulated by LPS or IFN. In contrast, IL-10 synergized with LPS and IFN to increase mRNA levels > or =9-fold and secreted A8 levels approximately 4-fold. IL-10 decreased the optimal time of mRNA expression induced by LPS from 24 to 8 h. Blocking experiments indicated that endogenous IL-10 contributes to gene induction by LPS. Cooperation between IL-10 and LPS was not due to altered mRNA stability but was dependent on de novo protein synthesis. Transfection analysis with A8 luciferase constructs confirmed that synergy was due to increased transcription. The region of the promoter involved was localized to a 178-bp fragment flanking the transcription start site of the gene. This region was also responsible for the suppressive effects of IL-4 and IL-13. Forskolin, CTP-cAMP, and PGE(2) also enhanced LPS- and IFN-induced A8 mRNA, whereas indomethacin significantly reduced synergy between IL-10 and LPS. Mitogen-activated protein kinase/cyclooxygenase 2/cAMP pathways involving CCAAT-enhancing binding protein, located within the active promoter, may mediate A8 gene up-regulation in a manner mechanistically distinct to genes regulated by IL-10 via the STAT pathway. A8 exhibits pleiotropic effects, and the high levels secreted as a result of IL-10 synergy may regulate untoward inflammatory damage by virtue of its an antioxidant capacity.
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PMID:Il-10 up-regulates macrophage expression of the S100 protein S100A8. 1134 60

IL-22 is an IFN-IL-10 cytokine family member, which is produced by activated Th1 and NK cells and acts primarily on epithelial cells. Here we demonstrate that IL-22, in contrast to its relative IFN-gamma, regulates the expression of only a few genes in keratinocytes. This is due to varied signal transduction. Gene expressions regulated by IL-22 should enhance antimicrobial defense [psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9)], inhibit cellular differentiation (e.g., profilaggrin, keratins 1 and 10, kallikrein 7), and increase cellular mobility [e.g., matrix metalloproteinease 1 (MMP1, collagenase 1), MMP3 (stromelysin 1), desmocollin 1]. In contrast, IFN-gamma favored the expression of MHC pathway molecules, adhesion molecules, cytokines, chemokines, and their receptors. The IL-22 effects were transcriptional and either independent of protein synthesis and secretion, or mediated by a secreted protein. Inflammatory conditions, but not keratinocyte differentiation, amplified the IL-22 effects. IL-22 application in mice enhanced cutaneous S100A9 and MMP1 expression. High IL-22 levels in psoriatic skin were associated with strongly up-regulated cutaneous S100A7, S100A8, S100A9, and MMP1 expression. Psoriatic patients showed strongly elevated IL-22 plasma levels, which correlated with the disease severity. Expression of IL-22 and IL-22-regulated genes was reduced by anti-psoriatic therapy. In summary, despite similarities, IFN-gamma primarily amplifies inflammation, while IL-22 may be important in the innate immunity and reorganization of epithelia.
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PMID:IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. 1661 90

S100A8 and S100A9 are intracellular calcium-binding proteins produced by myeloid cells that promote neutrophil/monocyte recruitment at inflamed tissues by enhancing attachment to endothelial cells. Although the intracellular functions of these proteins, i.e., myeloid-related proteins (MRP)-8 and MRP-14, are not completely understood, these proteins exhibit prominent extracellular cytokine-like functions and are considered reliable markers of inflammation in diverse diseases. As S100A8 and S100A9 have been reported to be rapidly released in response to components derived from infectious agents, we hypothesized that they play an important role in the modulation of key microbicidal phagocyte functions. In this study, we report for the first time that MRPs are powerful inducers of NO production by murine macrophages (Mphi). This increase in NO production was linked to an increased inducible NO synthase expression both at gene and protein level. This induction was concomitant with an important phosphorylation of SAPK/JNK, but also of MEK and ERK kinases. Upon stimulation with MRPs, NF-kappaB was rapidly translocated to the nucleus (30 min). When Mphi were treated concomitantly with IFN-gamma, another activator of Mphi functions, we observed a strong synergy in NO production, synergy that resulted from the engagement of exclusive signaling pathways: SAPK/JNK, ERK and NF-kappaB were involved in signaling of MRPs, whereas IFN-gamma uses the JAK/STAT pathway. This suggests that the synergy results from interactions of transcription factors in the promoter region. Finally, we observed this effect to be dependent on TLR4. Collectively, our study unravels the importance of MRPs as potent new inducers of Mphi NO production.
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PMID:Myeloid-related proteins rapidly modulate macrophage nitric oxide production during innate immune response. 1871 33

S100A8 and S100A9, highly expressed by neutrophils, activated macrophages, and microvascular endothelial cells, are secreted during inflammatory processes. Our earlier studies showed S100A8 to be an avid scavenger of oxidants, and, together with its dependence on IL-10 for expression in macrophages, we postulated that this protein has a protective role. S-nitrosylation is an important posttranslational modification that regulates NO transport, cell signaling, and homeostasis. Relatively few proteins are targets of S-nitrosylation. To date, no inflammation-associated proteins with NO-shuttling capacity have been identified. We used HPLC and mass spectrometry to show that S100A8 and S100A9 were readily S-nitrosylated by NO donors. S-nitrosylated S100A8 (S100A8-SNO) was the preferred nitrosylated product. No S-nitrosylation occurred when the single Cys residue in S100A8 was mutated to Ala. S100A8-SNO in human neutrophils treated with NO donors was confirmed by the biotin switch assay. The stable adduct transnitrosylated hemoglobin, indicating a role in NO transport. S100A8-SNO suppressed mast cell activation by compound 48/80; intravital microscopy was used to demonstrate suppression of leukocyte adhesion and extravasation triggered by compound 48/80 in the rat mesenteric microcirculation. Although S100A8 is induced in macrophages by LPS or IFN-gamma, the combination, which activates inducible NO synthase, did not induce S100A8. Thus, the antimicrobial functions of NO generated under these circumstances would not be compromised by S100A8. Our results suggest that S100A8-SNO may regulate leukocyte-endothelial cell interactions in the microcirculation, and suppression of mast cell-mediated inflammation represents an additional anti-inflammatory property for S100A8.
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PMID:S-nitrosylated S100A8: novel anti-inflammatory properties. 1883 21

Tracheal glands (TG) may play a specific role in the pathogenesis of cystic fibrosis (CF), a disease due to mutations in the cftr gene and characterized by airway inflammation and Pseudomonas aeruginosa infection. We compared the gene expression of wild-type TG cells and TG cells with the cftr DeltaF508 mutation (CF-TG cells) using microarrays covering the whole human genome. In the absence of infection, CF-TG cells constitutively exhibited an inflammatory signature, including genes that encode molecules such as IL-1alpha, IL-beta, IL-32, TNFSF14, LIF, CXCL1 and PLAU. In response to P. aeruginosa, genes associated with IFN-gamma response to infection (CXCL10, IL-24, IFNgammaR2) and other mediators of anti-infectious responses (CSF2, MMP1, MMP3, TLR2, S100 calcium-binding proteins A) were markedly up-regulated in wild-type TG cells. This microbicidal signature was silent in CF-TG cells. The deficiency of genes associated with IFN-gamma response was accompanied by the defective membrane expression of IFNgammaR2 and altered response of CF-TG cells to exogenous IFN-gamma. In addition, CF-TG cells were unable to secrete CXCL10, IL-24 and S100A8/S100A9 in response to P. aeruginosa. The differences between wild-type TG and CF-TG cells were due to the cftr mutation since gene expression was similar in wild-type TG cells and CF-TG cells transfected with a plasmid containing a functional cftr gene. Finally, we reported an altered sphingolipid metabolism in CF-TG cells, which may account for their inflammatory signature. This first comprehensive analysis of gene expression in TG cells proposes a protective role of wild-type TG against airborne pathogens and reveals an original program in which anti-infectious response was deficient in TG cells with a cftr mutation. This defective response may explain why host response does not contribute to protection against P. aeruginosa in CF.
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PMID:New microbicidal functions of tracheal glands: defective anti-infectious response to Pseudomonas aeruginosa in cystic fibrosis. 1939 82