Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation

Joseph W. Zagorski, Alexandra E. Turley, Robert A. Freeborn, Kelly R. VanDenBerg, Heather E. Dover, Brian R. Kardell, Karen T. Liby, Cheryl E. Rockwell

Research output: Research - peer-reviewArticle

Abstract

We previously demonstrated that activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) promotes CD4+ Th2 differentiation. In the current study, we assessed the role of Nrf2 in early events following T cell activation. The Nrf2 activators, tBHQ (tert-butylhydroquinone) and CDDO-Im (the imidazolide derivative of the triterpenoid CDDO), were used in conjunction with splenocytes derived from wild-type and Nrf2-null mice to distinguish between Nrf2-specific and off-target effects. CDDO-Im inhibited early IFNγ production in a largely Nrf2-dependent manner. In contrast, tBHQ and CDDO-Im had little effect on expression of CD25 or CD69. Furthermore, tBHQ inhibited GM-CSF and IL-2 production in both wild-type and Nrf2-null T cells, suggesting this effect is Nrf2-independent. Conversely, CDDO-Im caused a concentration-dependent increase in IL-2 secretion in wild-type, but not Nrf2-null, splenocytes, suggesting that Nrf2 promotes IL-2 production. Interestingly, both compounds inhibit NFκB DNA binding, where the suppression by tBHQ is Nrf2-independent and CDDO-Im is Nrf2-dependent. Surprisingly, as compared to wild-type splenocytes, Nrf2-null splenocytes showed lower nuclear accumulation of c-Jun, a member of the AP-1 family of transcription factors, which have been shown to drive multiple immune genes, including IL-2. Both Nrf2 activators caused a Nrf2-dependent trend toward increased nuclear accumulation of c-Jun. These data suggest that modulation of cytokine secretion by tBHQ likely involves multiple pathways, including AP-1, NFκB, and Nrf2. Overall, the data suggest that Nrf2 activation inhibits secretion of the Th1 cytokine IFNγ, and increases early production of IL-2, which has been shown to promote Th2 differentiation, and may support the later occurrence of Th2 polarization.

LanguageEnglish (US)
Pages67-76
Number of pages10
JournalBiochemical Pharmacology
Volume147
DOIs
StatePublished - Jan 1 2018

Profile

T-cells
Interleukin-2
Chemical activation
2-tert-butylhydroquinone
1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
T-Lymphocytes
Transcription Factor AP-1
Granulocyte-Macrophage Colony-Stimulating Factor
Cytokines
NF-E2 Transcription Factor
Transcription Factors
Genes
Modulation
Polarization
Derivatives
DNA
Null Lymphocytes

Keywords

  • CDDO-Im
  • IFNγ
  • IL-2
  • NFκB
  • Nrf2
  • T cell
  • tBHQ

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Zagorski, J. W., Turley, A. E., Freeborn, R. A., VanDenBerg, K. R., Dover, H. E., Kardell, B. R., ... Rockwell, C. E. (2018). Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. Biochemical Pharmacology, 147, 67-76. DOI: 10.1016/j.bcp.2017.11.005

Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. / Zagorski, Joseph W.; Turley, Alexandra E.; Freeborn, Robert A.; VanDenBerg, Kelly R.; Dover, Heather E.; Kardell, Brian R.; Liby, Karen T.; Rockwell, Cheryl E.

In: Biochemical Pharmacology, Vol. 147, 01.01.2018, p. 67-76.

Research output: Research - peer-reviewArticle

Zagorski JW, Turley AE, Freeborn RA, VanDenBerg KR, Dover HE, Kardell BR et al. Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. Biochemical Pharmacology. 2018 Jan 1;147:67-76. Available from, DOI: 10.1016/j.bcp.2017.11.005
Zagorski, Joseph W. ; Turley, Alexandra E. ; Freeborn, Robert A. ; VanDenBerg, Kelly R. ; Dover, Heather E. ; Kardell, Brian R. ; Liby, Karen T. ; Rockwell, Cheryl E./ Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. In: Biochemical Pharmacology. 2018 ; Vol. 147. pp. 67-76
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