Tolerance versus immune response -- microRNAs as important elements in the regulation of the HLA-G gene expression.
HLA-G is a class Ib HLA which has gained much attention due to its multiple functions on the immune system. HLA-G exerts several immunomodulatory effects, being beneficially implicated in embryo implantation and fetal survival but, conversely, being potentially detrimental in tumors and viral infections. Such a two-edged sword behavior suggest that HLA-G expression is under tight regulation. However, to date, little is known about the regulation of this gene and previous works have been unable to well correlate HLA-G regulation at the mRNA level with the polymorphic variants at the genomic level. Here we present the hypothesis that an element, which was until now neglected, might play a role in HLA-G expression regulation: MicroRNAs might participate in the regulation of the HLA-G gene expression through a putative microRNA binding site at its 3' UTR region. Inside the 20 nt region of this microRNA binding site lies a C/G polymorphism, which was shown to be responsible for differential microRNA binding affinity and translation suppression. The role of microRNA binding on the regulation of HLA-G gene expression (and therefore on tolerance versus immune response) can be easily tested through relatively simple steps: Confirming the expression of those three complementary microRNAs in human cells which express HLA-G, followed by examination of the correlation between HLA-G mRNA and protein production controlling for HLA-G genotypes and microRNA levels; finally, selective inhibition of microRNA activity with anti-sense oligos restoring HLA-G production would access microRNA influence on HLA-G expression which, if confirmed, might help in the development of strategies to the management of several conditions in which HLA-G is involved, including pregnancy complications, transplantation, and cancer.
Veit
T D
TD
Genetics Department, Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Chies
J A B
JA
D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006084:Graft Rejection / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D007109:Immunity / Q000235:genetics* / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000276:immunology; D014181:Transplantation Immunology
D020413:3' Untranslated Regions; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D035683:MicroRNAs