Cytotoxicity, Immunologic HLA-G Antigens Histocompatibility Antigens Class I/drug effects/metabolism
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.
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.