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* Norwegian University of Science and Technology, Institute of Cancer Research and Molecular Medicine, Trondheim, Norway;
Research Institute for Internal Medicine, Faculty Division Rikshospitalet, University of Oslo and Section of Clinical Immunology and Infectious Diseases, Medical Department, Rikshospitalet Medical Center and Faculty Division Rikshospitalet, University of Oslo, Norway;
NovImmune SA, Geneva, Switzerland,
University of Massachusetts Medical School, Department of Medicine, Division of Infectious Diseases and Immunology, Worcester, MA 01605; and
¶ Department of Infectious Diseases, Ullevaal University Hospital, Oslo, Norway
Soluble proteins that bind LPS, like myeloid differentiation-2 (MD-2) and CD14, have essential roles in regulating LPS signaling through TLR4. During a Gram-negative bacterial infection, the host may control the response by adjusting the levels of soluble MD-2 and CD14. To address the surface expression of MD-2 on human leukocytes, we developed a mAb, IIC1, that recognized MD-2 both free and when bound to TLR4. MD-2 was found on the surface of freshly isolated monocytes, on a subpopulation of CD19+ B-cells and on CD15+ neutrophils. LPS transiently reduced the MD-2 levels on monocytes, which is most likely due to endocytosis of the LPS receptor complex since MD-2 colocalized with TLR4 in early endosomes after LPS stimulation. In the absence of LPS, MD-2 partly colocalized with TLR4 in Golgi trans and medial compartments. Cultivating monocytes for 18–20 h resulted in loss of MD-2 expression on the surface, which was reversed either by LPS or IL-10. Furthermore, addition of IL-10, but not LPS, resulted in a considerable increase in mRNA for both MD-2 and CD14. Using ELISA, we demonstrated that IL-10 had a profound dose- and time-related effect on the release of soluble MD-2 and soluble CD14 from monocytes. In HIV-infected patients, the amounts of MD-2, CD14, and IL-10 increased significantly in the patient group with AIDS. Of interest, we found that IL-10, CD14, and MD-2 levels were positively correlated, suggesting that IL-10 may be a driving force for increased release of MD-2 and CD14 during systemic inflammation.
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 funded by The Research Council of Norway, the Norwegian Cancer Society, and the Commission of the European Communities, LSMH-CT-2004-512093, AMIS.
2 Address correspondence and reprint requests to Dr. Terje Espevik, Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Olav Kyrres gt. 9, N-7489 Trondheim, Norway. E-mail address: terje.espevik{at}ntnu.no
3 Abbreviations used in this paper: TIR, Toll/IL-1 receptor/resistance; MD-2, myeloid differentiation-2; MAC, Mycobacterium avium complex; r, recombinant; sMD-2, soluble MD-2; sCD14, soluble CD14.
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  P. Tissieres, T. Araud, A. Ochoda, G. Drifte, I. Dunn-Siegrist, and J. Pugin Cooperation between PU.1 and CAAT/Enhancer-binding Protein {beta} Is Necessary to Induce the Expression of the MD-2 Gene J. Biol. Chem., September 25, 2009; 284(39): 26261 - 26272. [Abstract] [Full Text] [PDF]
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