Regulation of S100A8 by glucocorticoids.
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.
Hsu
Kenneth
K
Inflammatory Diseases Research Unit, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Passey
Robert J
RJ
Endoh
Yasumi
Y
Rahimi
Farid
F
Youssef
Peter
P
Yen
Tina
T
Geczy
Carolyn L
CL
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D040501:Calgranulin A; D040502:Calgranulin B / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements / Q000235:genetics; D009418:S100 Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D040501:Calgranulin A; D040502:Calgranulin B; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D009418:S100 Proteins; C086145:S100a8 protein, mouse; D003907:Dexamethasone; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003345:Corticosterone; D006854:Hydrocortisone