The Nrf2 activator, tBHQ, differentially affects early events following stimulation of Jurkat cells.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is activated by cellular stresses, such as oxidative compounds. After activation, Nrf2 induces transcription of its target genes, many of which have cytoprotective functions. Previously, we have shown that activation of Nrf2 by tert-butylhydroquinone (tBHQ) skews murine CD4⁺ T-cell differentiation. Although the role of Nrf2 in murine T cells is somewhat characterized, it is largely uncharacterized in human T cells. Therefore, the aim of the current studies was to characterize the effects of the Nrf2 activator, tBHQ, on the early events of human CD4⁺ T-cell activation. Pretreatment of Jurkat T cells with tBHQ, prior to activation with anti-CD3/anti-CD28, diminished the production of interleukin-2 (IL-2) at both the transcript and protein levels. Similarly, the expression of CD25 also diminished, albeit to a lesser degree than IL-2, after pretreatment with tBHQ. The decrease in IL-2 production was not due to decreased nuclear translocation of c-fos or c-jun. Although tBHQ caused both a delay and a decrease in Ca²⁺ influx in activated Jurkat cells, no decrease in nuclear factor of activated T cells (NFAT) DNA binding or transcriptional activity was observed. In contrast to NFAT, tBHQ significantly decreased NFκB transcriptional activity. Collectively, our studies show that the Nrf2 activator, tBHQ, inhibits IL-2 and CD25 expression, which correlates with decreased NFκB transcriptional activity in activated Jurkat cells. Overall, our studies suggest that Nrf2 represents a novel mechanism for the regulation of both human and mouse T cell function.
* Department of Pharmacology & Toxicology.
Joseph W
JW
Zagorski
Alexandra E
AE
Turley
Heather E
HE
Dover
Kelly R
KR
VanDenBerg
Jacob R
JR
Compton
Cheryl E
CE
Rockwell
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D006873:Hydroquinones; D007155:Immunologic Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000099192:CD69 Antigens; C508594:IL2 protein, human; C508017:IL2RA protein, human; C495635:NFE2L2 protein, human; C018855:2-tert-butylhydroquinone
IL-2; NFĸB; Nrf2; T cell.; calcium; tBHQ