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Nuclear factor erythroid 2‐related factor 2 (Nrf2) activators inhibit pro‐inflammatory cytokine production by murine T cells
Author(s) -
Rockwell Cheryl Elizabeth,
Fields Patrick,
Klaassen Curtis
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.755.4
Subject(s) - transcription factor , activator (genetics) , chemistry , microbiology and biotechnology , cytokine , biology , immunology , biochemistry , gene
Nrf2 is a transcription factor upregulating cytoprotective genes in response to cellular stress. Nrf2 mRNA is upregulated in mature CD3 + cells by the Nrf2 activator, tert‐butylhydroquinone (tBHQ). In addition, tBHQ induces expression of the Nrf2 target genes, Ho‐1, Nqo1, and Gclc in wild‐type, but not Nrf2‐null CD3 + T cells, suggesting the induction is Nrf2‐dependent. Furthermore, tBHQ and butylated hydroxyanisole (BHA), another Nrf2 activator, markedly inhibit IFNγ transcription in wild‐type activated T cells, but have little effect upon IFNγ transcription in Nrf2‐null T cells. Likewise, tBHQ inhibits binding to both the AP‐1 and NFκB response elements in wild‐type CD3 + cells, but only modestly inhibits AP‐1/NFκB binding in Nrf2‐null CD3 + cells, suggesting the effects on the AP‐1 and NFκB binding sites are partially Nrf2‐dependent. In addition to its effects upon IFNγ, tBHQ also inhibits production of TNFα and IL‐2 by activated T cells. Collectively, the current studies suggest Nrf2 activation in CD3 + cells markedly inhibits IFNγ transcription, which is likely due in part to decreased binding to the AP‐1 and NFκB response elements. Overall, the present studies suggest Nrf2 may represent a novel regulatory mechanism in mature murine T cells and thus may be a useful target for the development of new anti‐inflammatory therapeutics. (Supported by NIH grants ES09716, ES07079, ES013714, ES09649, and RR021940.)