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Mechanism of the Salutary Effects of Estrogen on Kupffer Cell Phagocytic Capacity following Trauma-Hemorrhage: Pivotal Role of Akt Activation¹

Center for Surgical Research and Department of Surgery, University of Alabama, Birmingham, AL 35294

Kupffer cells are macrophages in the liver whose major role is to clear circulating pathogens. Decreased phagocytic capacity of Kupffer cells may result in severe systemic infection. We tested the hypothesis that the depressed Kupffer cell phagocytic capacity following trauma-hemorrhage is enhanced by estrogen administration and this occurs due to maintenance of Fc receptor expression and cellular ATP content via the activation of Akt. Male C3H/HeN mice were subjected to sham operation or trauma-hemorrhage and sacrificed 2 h thereafter. Estrogen, with or without an estrogen receptor antagonist (ICI 182,780), a PI3K inhibitor (Wortmannin), or vehicle, was injected during resuscitation. Kupffer cell phagocytic capacity was tested in vivo. The expression of Fc receptors, of Akt phosphorylation, of p38 MAPK phosphorylation, of DNA binding activity of NF-B and ATP content of Kupffer cells were also determined. Trauma-hemorrhage suppressed Kupffer cell phagocytosis by decreasing Fc receptor expression and Akt activation; however, it induced p38 MAPK activation and increased NF-B activity. Cellular ATP levels were also decreased following trauma-hemorrhage. Administration of estrogen following trauma-hemorrhage increased phospho-Akt levels and normalized all the parameters described as well as plasma levels of TNF-, IL-6, and IL-10. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of estrogen in improving the phagocytic capacity of Kupffer cells following trauma-hemorrhage. Thus, activation of Akt plays a crucial role in mediating the salutary effect of estrogen in restoring trauma-hemorrhage-induced suppression of Kupffer cell phagocytosis.

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 Grant R01 GM37127 from the National Institutes of Health (to I.H.C.).

² C.-H.H. and E.A.N. contributed equally to this manuscript.

³ Current address: Department of Trauma and Emergency Surgery and Department of Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan 40402, Republic of China.

⁴ Address correspondence and reprint requests to Dr. Irshad H. Chaudry, Center for Surgical Research, G094 Volker Hall, University of Alabama, 1670 University Boulevard, Birmingham, AL 35294-0019. E-mail address: Irshad.Chaudry{at}ccc.uab.edu

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