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Chronic Estradiol Administration In Vivo Promotes the Proinflammatory Response of Macrophages to TLR4 Activation: Involvement of the Phosphatidylinositol 3-Kinase Pathway¹

Bertrand Calippe^*, Victorine Douin-Echinard^*, Muriel Laffargue, Henrik Laurell^*, Vanessa Rana-Poussine^*, Bernard Pipy, Jean-Charles Guéry, Francis Bayard^*, Jean-François Arnal^* and Pierre Gourdy^2,*,

^* Institut National de la Santé et de la Recherche Médicale U858, Institut de Médecine Moléculaire de Rangueil, IFR31, Toulouse, Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie de Toulouse Purpan, IFR30, Toulouse, Centre Hospitalier Universitaire 2405, IFR31, Université Paul Sabatier, Toulouse, and Service de Diabétologie, Pôle Cardio-Vasculaire et Métabolique, Unité Propre à I’Enseignement Supérieur Associée Toulouse Rangueil, France

Short-term exposure to 17β-estradiol (E2) in vitro has been reported to decrease the production of proinflammatory cytokines by LPS-activated macrophages through estrogen receptor (ER)-dependent activation of the PI3K pathway. In the present study, we confirm that in vitro exposure of mouse peritoneal macrophages to E2 enhanced Akt phosphorylation and slightly decreased LPS-induced cytokine production. In striking contrast, we show that chronic administration of E2 to ovariectomized mice markedly increases the expression of IL-1β, IL-6, IL-12p40, and inducible NO synthase by resident peritoneal macrophages in response to LPS ex vivo. These results clearly indicate that short-term E2 treatment in vitro does not predict the long-term effect of estrogens in vivo on peritoneal macrophage functions. We show that this in vivo proinflammatory effect of E2 was mediated through ER. Although the expression of components of the LPS-recognition complex remained unchanged, we provided evidences for alterations of the TLR4 signaling pathway in macrophages from E2-treated mice. Indeed, E2 treatment resulted in the inhibition of PI3K activity and Akt phosphorylation in LPS-activated macrophages, whereas NF-B p65 transcriptional activity was concomitantly increased. Incubation of macrophages with the PI3K inhibitor wortmanin enhanced proinflammatory cytokine gene expression in response to TLR4 activation, and abolishes the difference between cells from placebo- or E2-treated mice, demonstrating the pivotal role of the PI3K/Akt pathway. We conclude that the macrophage activation status is enhanced in vivo by E2 through ER and, at least in part, by the down-modulation of the PI3K/Akt pathway, thereby alleviating this negative regulator of TLR4-signaling.

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 was supported by a grant from the Agence Nationale de la Recherche (06-Physio-010), Institut National de la Santé et de la Recherche Médicale, European Vascular Genomics Network n° 503254, Fondation de France, University Paul Sabatier Toulouse 3, and the Conseil Régional Midi-Pyrénées. P.G. has been supported by a grant (Contrat Interface) from Institut National de la Santé et de la Recherche Médicale.

B. Calippe and P. Gourdy designed and performed research, analyzed data and wrote the paper. V. Douin-Echinard, M. Laffargue, H. Laurell, and V. Rana-Poussine performed some experiments and analyzed corresponding data. F. Bayard, J. F. Arnal, J. C. Guéry, and B. Pipy designed the research and reviewed the data and the manuscript.

² Address correspondence and reprint requests to Dr. Pierre Gourdy, Institut National de la Santé et de la Recherche Médicale U858, Institut de Médecine Moléculaire de Rangueil, Boîte Postale 84225, 31432 Toulouse Cedex 4, France. E-mail address: gourdyp{at}toulouse.inserm.fr

³ Abbreviations used in this paper: ER, estrogen receptor; iNOS, inducible NO synthase; qRT-PCR, quantitative real time-PCR; PLSD, protected least significant difference.

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