Regulation of the lipopolysaccharide signal transduction pathway by 17beta-estradiol in macrophage cells.
We have previously shown that 17beta-estradiol (E2) prevents the activation of brain macrophages, i.e. microglia cells, both in vitro and in vivo. Hormone exerts this inhibitory effect by inhibiting pro-inflammatory gene expression. In this study we further investigated on the molecular mechanism of E2 action in the RAW 264.7 macrophage cell line. We show here that these cells express the alpha-isoform of the estrogen receptor (ERalpha) and not ERbeta. Similarly to its activity in brain macrophages, E2 is able to inhibit the activation program induced by lipopolysaccharide (LPS) in RAW 264.7 cells, as shown by the inhibitory effect of hormone on the morphological conversion and matrix metalloproteinase-9 (MMP-9) expression induced by the endotoxin. In addition, we demonstrate that hormone treatment is not associated with a reduction in the steady-state expression of Toll-like receptor-4 (TLR-4) and CD14, two components of the LPS receptor complex. Our results further confirm the anti-inflammatory role of ERalpha in macrophages and propose that the mechanism of hormone action on macrophage reactivity involves signaling molecules which are down-stream effectors of the LPS membrane receptors.
Vegeto
Elisabetta
E
Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti, 9 20133, Italy.
Ghisletti
Serena
S
Meda
Clara
C
Etteri
Sabrina
S
Belcredito
Silvia
S
Maggi
Adriana
A
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D004958:Estradiol; D020780:Matrix Metalloproteinase 9