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Cutting Edge: Progesterone Regulates IFN- Production by Plasmacytoid Dendritic Cells¹

Grant C. Hughes^2,*,, Sunil Thomas^3,, Chang Li^3,, Murali-Krishna Kaja^, and Edward A. Clark^,

^* Department of Medicine, Division of Rheumatology, Department of Immunology, National Regional Primate Research Center, University of Washington, Seattle, WA 98195

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- upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN- production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN- 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- 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- production by pDCs, Pg may regulate antiviral immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work supported by National Institutes of Health Grants AI44257, RR00166, A152203, AR7108, AI53146, and AI51386.

² Address correspondence and reprint requests to Dr. Grant C. Hughes, Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA 98195. E-mail address: hughesg{at}u.washington.edu

³ S.T. and C.L. contributed equally to this work.

⁴ Abbreviations used in this paper: Pg, progesterone, DMPA, depot medroxyprogesterone acetate; BDCA, blood dendritic cell Ag; BMDC, bone marrow-derived DC; DC, dendritic cell; Dex, dexamethasone; E2, estradiol; mDC, myeloid DC; IRF, IFN regulatory factor; MPA, medroxyprogesterone acetate; mPDCA1, murine pDC Ag 1; pDC, plasmacytoid DC; p(I:C), polyinosinic:polycitidylic acid; RIG-I, retinoic acid-inducible gene I; VSV, vesicular stomatitis virus.