Early immune response and regulation of IL-2 receptor subunits

Millie Hughes-Fulford, Eiko Sugano, Thomas Schopper, Chai-Fei Li, J. B. Boonyaratanakornkit, Augusto Cogoli

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Affymetrix oligonucleotide arrays were used to monitor expression of 8796 genes and probe sets in activated T-cells; analysis revealed that 217 genes were significantly upregulated within 4 h. Induced genes included transcription factors, cytokines and their receptor genes. Analysis by semi-quantitative RT-PCR confirmed the significant induction of IL-2, IL-2Rγ and IL-2Rα. Forty-eight of the 217 induced genes are known to or predicted to be regulated by a CRE promoter/enhancer. We found that T-cell activation caused a significant increase in CREB phosphorylation furthermore, inhibition of the PKC pathway by GF109203 reduced CREB activation by 50% and inhibition of the PKA pathway caused a total block of CREB phosphorylation and significantly reduced IFNγ, IL-2 and IL-2Rα gene expression by approximately 40% (p<0.001). PKCθ plays a major role in T-cell activation: inhibition of PKC significantly reduced the expression of IFNγ, IL-2 and IL-2Rα. Since PKC blocked activation of CREB, we studied potential cross-talk between the PKC and the PKA/MAPK pathways, PMA-stimulated Jurkat cells were studied with specific signal pathway inhibitors. Extracellular signal-regulated kinase-2 (ERK2) pathway was found to be significantly activated greater than seven-fold within 30 min; however, there was little activation of ERK-1 and no activation of JNK or p38 MAPK. Inhibition of the PKA pathway, but not the PKC pathway, resulted in inhibition of ERK1/2 activation at all time points, inhibition of MEK1 and 2 significantly blocked expression of IL-2 and IL-2Rα. Gene expression of IL-2Rα and IFNγ was dependent on PKA in S49 wt cells but not in kin- mutants. Using gel shift analysis, we found that forskolin activation of T-cells resulted in activation of AP1 sites; this increase in nuclear extract AP1 was significantly blocked by MEK1 inhibitor U0126. Taken together, these results suggest that the PKA in addition to PKC and MAPK pathways plays a role in early T-cell activation and induction of IL-2, IL-2Rα and IFNγ gene expression.

Original languageEnglish (US)
Pages (from-to)1111-1124
Number of pages14
JournalCellular Signalling
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

Keywords

  • IL-2 receptor
  • IL-2 receptor subunits
  • Immune response
  • Interleukin-2
  • Protein kinase A
  • T-cell activation

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Hughes-Fulford, M., Sugano, E., Schopper, T., Li, C-F., Boonyaratanakornkit, J. B., & Cogoli, A. (2005). Early immune response and regulation of IL-2 receptor subunits. Cellular Signalling, 17(9), 1111-1124. https://doi.org/10.1016/j.cellsig.2004.12.016