Cell-specific regulation of PTX3 by glucocorticoid hormones in hematopoietic and nonhematopoietic cells.
PTX3 (prototypic long pentraxin 3) is a fluid phase pattern recognition receptor, which plays nonredundant roles in the resistance against diverse pathogens, in the assembly of a hyaluronic acid-rich extracellular matrix, and in female fertility. Inflammatory signals induce production of PTX3 in diverse cell types, including myeloid dendritic cells (DC), fibroblasts, and endothelial cells (EC). The present study was designed to explore the effect of glucocorticoid hormones (GC) on PTX3 production in different cellular contexts. In myeloid DC, GC inhibited the PTX3 production. In contrast, in fibroblasts and EC, GC alone induced and, under inflammatory conditions, enhanced and extended PTX3 production. In vivo administration of GC augmented the blood levels of PTX3 in mice and humans. Moreover, patients with Cushing syndrome had increased levels of circulating PTX3, whereas PTX3 levels were decreased in subjects affected by iatrogenic hypocortisolism. In nonhematopoietic cells, GC receptor (GR) functioned as a ligand-dependent transcription factor (dimerization-dependent) to induce PTX3 gene expression. In contrast, in hematopoietic cells, GR repressed PTX3 gene transcription by interfering (dimerization-independent) with the action of other signaling pathways, probably NFkappaB and AP-1. Thus, divergent effects of GC were found to be due to different GR mechanisms. The results presented here indicate that GC have divergent effects on PTX3 production in hematopoietic (DC and macrophages) and nonhematopoietic (fibroblasts and EC) cells. The divergent effects of GC on PTX3 production probably reflect the different functions of this multifunctional molecule in innate immunity and in the construction of the extracellular matrix.
Doni
Andrea
A
Istituto Clinico Humanitas, Istituto Di Ricerca Cura a Caratte Re Scientifico, Department of Immunology and Inflammation, Rozzano, Milan, Italy. andrea.doni@humanitas.it
Mantovani
Giovanna
G
Porta
Chiara
C
Tuckermann
Jan
J
Reichardt
Holger M
HM
Kleiman
Anna
A
Sironi
Marina
M
Rubino
Luca
L
Pasqualini
Fabio
F
Nebuloni
Manuela
M
Signorini
Stefano
S
Peri
Giuseppe
G
Sica
Antonio
A
Beck-Peccoz
Paolo
P
Bottazzi
Barbara
B
Mantovani
Alberto
A
D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007107:Immune System; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D014158:Transcription, Genetic; D000099153:Pentraxins
D002097:C-Reactive Protein; D005938:Glucocorticoids; D008024:Ligands; D000683:Serum Amyloid P-Component; D000099153:Pentraxins