Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

作者：Young Nicholas A; Friedman Alexandra K; Kaffenberger Benjamin; Rajaram Murugesan V S; Birmingham Daniell J; Rovin Brad H; Hebert Lee A; Schlesinger Larry S; Wu Lai Chu; Jarjour Wael N^*

来源：Molecular Immunology, 2013, 54(1): 23-31.

DOI：10.1016/j.molimm.2012.10.026

• Systemic lupus erythematosus
• Estrogen
• ZAS3
• Autoimmunity

Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) alpha and beta into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ER alpha binding to putative EREs within the ZAS3 gene and ER alpha knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFN alpha has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.

• 出版日期2013-5