Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu
Keywords: 
Cytotoxicity, Immunologic
HLA-G Antigens
Histocompatibility Antigens Class I/drug effects/metabolism
Issue Date: 
2009
Publisher: 
Blackwell Publishing
ISSN: 
0019-2805
Citation: 
Diaz-Lagares A, Alegre E, LeMaoult J, Carosella ED, Gonzalez A. Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu. Immunology 2009 Mar;126(3):436-445.
Abstract
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.

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