Gata1 overexpression in neurons increases the expression of cell-mediated cytotoxicity-related genes

Abstract

Cell-mediated immune activation and inflammation have been suggested as key pathophysiological mediators of illness caused by stress and major depressive disorder (MDD). Previous studies have shown that MDD is an inflammatory disorder because plasma levels of pro-inflammatory cytokines are increased in the depressed patients. We have conducted studies to characterize differentially expressed genes in postmortem prefrontal cortex (PFC) of MDD. In the current study, using Gene Ontology analysis, we have identified that natural killer cell-mediated cytotoxicity' pathway genes are overrepresented in the set of up-regulated genes in the PFC of MDD. To determine if altered gene expression is relevant to Gata1, we tested whether several natural killer (NK) cell cytotoxicity genes are up-regulated in cultured neurons by Gata1 overexpression. We found that the mRNA expression of class-I restricted T cell associated molecule (Crtam), nuclear factor, interleukin 3 regulated (Nfil3), and granzyme B (Gzmb) were significantly increased by the Gata1 overexpression in the cultured cortical neurons. Crtam is an immune receptor that is primarily expressed on activated cytotoxic lymphocytes, including NK cells and CD8+T cells. Nfil3 is a transcription factor that affects the development of NK cells, and Gzmb is a serine protease that is produced by cytotoxic T cells and NK cells. These results suggest that cell-mediated immune activation is involved in the pathological mechanisms of MDD, and that Gata1 may be associated with immune activation in the central nervous system.