The role of TNFα pathway and microRNA in regulating autoimmune regulator gene expression and translation (P4101)

Abstract Autoimmune regulator (AIRE) is a responsible gene for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting multiple autoimmune diseases. AIRE gene is expressed in the thymus and lymph nodes. Thus, AIRE gene plays an important role in both the central and peripheral regulation of immune responses. However, there are some patients with APECED, who lack mutations in AIRE gene. Therefore, dysfunction of the regulatory mechanism of AIRE gene may be associated with the pathogenesis of APECED. In this study, we found that nuclear factor-κB (NF-κB) pathway regulated AIRE gene expression during maturation process of dendritic cells under TNFα stimulation, along with the significant elevation of AIRE gene expression. By inhibiting NF-κB pathway, AIRE gene expression was decreased. We also found that miR-220b inhibited the translation of AIRE gene, binding 3’ untranslated region (3’UTR) of the target mRNA. AIRE protein expression was inhibited by overexpressing microRNAs in 293T cells transfected with AIRE gene which have 3’UTR plasmid but not in AIRE open reading frame (ORF) alone. At least, miR-220b was not expressed in the normal thymus which expresses high level of both AIRE gene and AIRE protein, to delete autoreactive T cells. Thus, it was concluded that there are multiple the regulatory mechanisms of AIRE gene expression, and deterioration of those mechanisms may be associated with APECED phenotype.