Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone.
The role of progesterone in modulating dendritic cell (DC) function following stimulation of different TLRs is relatively unknown. We compared the ability of progesterone to modulate murine bone marrow-derived DC cytokine production (IL-6 and IL-12) and costimulatory molecule expression (CD40, CD80, and CD86) induced by either TLR3 or TLR4 ligation and determined whether activity was via the progesterone receptor (PR) or glucocorticoid receptor (GR) by comparative studies with the PR-specific agonist norgestrel and the GR agonist dexamethasone. Progesterone was found to downregulate, albeit with different sensitivities, both TLR3- and TLR4-induced IL-6 production entirely via the GR, but IL-12p40 production via either the GR or PR. Of particular significance was that progesterone was able to significantly inhibit TLR3- but not TLR4-induced CD40 expression in bone marrow-derived DCs. Stimulation of the PR (with progesterone and norgestrel) by pretreatment of DCs was found to sustain IFN regulatory factor-3 phosphorylation following TLR3 ligation, but not TLR4 ligation. Overall, these studies demonstrate that progesterone can differentially regulate the signaling pathways employed by TLR3 and TLR4 agonists to affect costimulatory molecule expression and cytokine production.
Jones
Leigh A
LA
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
Kreem
Shrook
S
Shweash
Muhannad
M
Paul
Andrew
A
Alexander
James
J
Roberts
Craig W
CW
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000276:immunology / Q000378:metabolism; D011980:Receptors, Progesterone / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D011374:Progesterone