Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu
Angel Díaz-Lagares (1), Estibaliz Alegre [SP] (1), Joel LeMaoult (2), Edgardo D. Carosella (2) and Álvaro González [SP](1)
(1) Department of Biochemistry, University Clinic of Navarra, Pamplona, Spain
(2) Service de Recherches en Hémato-Immunologie, CEA-DSV-DRM, Institut Universitaire d?He´matologie, Hopital Saint Louis, Paris, France
Date: Mar 1, 2009Biochemistry [SP]
Human leucocyte antigen G (HLA-G) is a tolerogenic molecule that protects the fetus from maternal immune attack, may favour tumoral immunoescape and is up-regulated in viral and inflammatory diseases. The aim of this work was to discover if nitric oxide (NO) could affect HLA-G expression or function because NO is an important modulator of innate and adaptive immunity.
For this purpose HLA-G expression and function were analysed following treatment with a NO donor or a peroxynitrite donor in various cell lines expressing HLA-G either spontaneously or upon transfection. Results showed NO-dependent nitration of both cellular and soluble HLA-G protein, but not all HLA-G moieties underwent nitration. Endogenous biosynthesis of NO by both U-937-HLA-G1 and M8-HLA-G5 stable transfectants also caused HLA-G nitration.
The NO decreased total HLA-G cellular protein content and expression on the cell surface, while increasing HLA-G shedding into the culture medium. This effect was post-transcriptional and the result of metalloprotease activity. By contrast, NO pretreatment did not affect HLA-G capability to suppress NK cytotoxicity and lymphocyte proliferation.
Our studies show that NO regulates the availability of HLA-G molecules without modifying their biological activities.
CITATION Immunology. 2009 Mar;126(3):436-45
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