Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells.
Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman's risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-alpha upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-alpha production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-alpha production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-alpha induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-alpha production by pDCs, Pg may regulate antiviral immunity.
Hughes
Grant C
GC
Department of Medicine, Division of Rheumatology, National Regional Primate Research Center, University of Washington, Seattle, WA 98195, USA. hughesg@u.washington.edu
Thomas
Sunil
S
Li
Chang
C
Kaja
Murali-Krishna
MK
Clark
Edward A
EA
D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D054243:Vesicular Stomatitis / Q000139:chemically induced / Q000276:immunology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology
D016898:Interferon-alpha; D051193:Toll-Like Receptors; D011374:Progesterone; D017258:Medroxyprogesterone Acetate