Abstract
S100A8 (A8) has roles in inflammation, differentiation and development and is associated with oxidative defense. Murine A8 (mA8) is up-regulated in macrophages, fibroblasts, and microvascular endothelial cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these cells. Relative to stimulation by LPS, GCs increased mA8 gene transcription and mRNA half-life. Enhancement required new protein synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C negatively regulated this process. Promoter analysis indicated element(s) essential for LPS and dexamethasone enhancement colocated within the region -178 to 0 bp. In the absence of glucocorticoid response elements, NF1 motif at -58 is a candidate for mediation of enhancement. Gel shift analysis detected no differences between LPS- and LPS/dexamethasone-treated complexes within this region. GCs increased constitutive levels of A8 and S100A9 (A9) mRNA in human monocytes. The synovial membrane of rheumatoid patients treated with high dose i.v. methylprednisolone contained higher numbers of A8/A9-positive macrophages than pre- or posttreatment samples. Results support the proposal that A8 has anti-inflammatory properties that may be independent of hetero-complex formation with A9 and may also enable localized defense in the absence of overriding deleterious host responses.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / physiology*
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Animals
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism
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Arthritis, Rheumatoid / pathology
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Calgranulin A
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Calgranulin B / biosynthesis
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Calgranulin B / genetics
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Cell Line
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Cell Line, Tumor
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Corticosterone / genetics
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Corticosterone / metabolism
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Corticosterone / physiology
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Cyclic AMP / physiology
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Cyclooxygenase 2
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Dexamethasone / metabolism
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Dexamethasone / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Glucocorticoids / genetics
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Glucocorticoids / metabolism
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Glucocorticoids / physiology*
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Humans
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Hydrocortisone / genetics
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Hydrocortisone / metabolism
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Hydrocortisone / physiology
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Lipopolysaccharides / metabolism
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Lipopolysaccharides / pharmacology
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Membrane Proteins
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Mice
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Prostaglandin-Endoperoxide Synthases / physiology
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RNA Stability / drug effects
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RNA Stability / immunology
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RNA, Messenger / biosynthesis
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Response Elements / genetics
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S100 Proteins / biosynthesis*
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S100 Proteins / genetics
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Synovial Membrane / immunology
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Synovial Membrane / metabolism
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Synovial Membrane / pathology
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Transcription, Genetic / drug effects
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Transcription, Genetic / immunology
Substances
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Adjuvants, Immunologic
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Calgranulin A
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Calgranulin B
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Glucocorticoids
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Lipopolysaccharides
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Membrane Proteins
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RNA, Messenger
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S100 Proteins
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S100a8 protein, mouse
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Dexamethasone
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Cyclic AMP
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Corticosterone
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Hydrocortisone