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The Role of Hepatic Invariant NKT Cells in Systemic/Local Inflammation and Mortality during Polymicrobial Septic Shock¹

Caroline K. Hu^2,*, Fabienne Venet^2,*, David S. Heffernan^*, Yvonne L. Wang^*, Brian Horner, Xin Huang^*, Chun-Shiang Chung^*, Stephen H. Gregory and Alfred Ayala^3,*

^* Shock-Trauma Research Laboratories, Division of Surgical Research, Department of Surgery, and Department of Internal Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903

NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (J18^–/–) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3⁺-galactosylceramide CD1d tetramer⁺ cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.

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 Grants R01 GM46354 (to A.A.) and DK68097 (to S.H.G.) from the National Institutes of Health.

² C.K.H. and F.V. contributed equally as first authors to this work.

³ Address correspondence and reprint requests to Dr. Alfred Ayala, Division of Surgical Research, Aldrich 227, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: AAYALA{at}LIFESPAN.org

⁴ Abbreviations used in this paper: CLP, cecal ligation and puncture; -GalCer, -galactosylceramide; iNKT, invariant NKT; MFI, mean fluorescence intensity; NPC, nonparenchymal cell.