Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3

Hayley D. Woolson, Victoria S. Thomson, Claire Rutherford, Stephen J Yarwood, Timothy M. Palmer

    Research output: Contribution to journalArticle

    37 Citations (Scopus)

    Abstract

    Here we demonstrate that elevation of cyclic AMP (cAMP) levels in human umbilical vein endothelial cells (HUVECs) specifically attenuates ERK1,2 activation in response to either leptin or a soluble interleukin IL-6 receptor-alpha/IL-6 (sIL-6R alpha/IL-6) trans-signalling complex but not protein kinase C activator phorbol 12-myristate 13-acetate. The inhibitory effects of cAMP on sIL-6R alpha/IL-6-stimulated phosphorylation of ERK1,2 and STAT3 were abolished by either short interfering (si) RNA-mediated knockdown or genetic ablation of suppressor of cytokine signalling-3 (SOCS-3). The inhibitory effect of cAMP could not be reversed by inhibition of cAMP-dependent protein kinase (PKA) but was blocked by depletion of the alternative intracellular cAMP sensor exchange protein activated by cAMP 1 (Epac1), which is also required to observe SOCS-3 accumulation in response to cAMP. Interestingly, the ability of cAMP elevation to inhibit IL-6 signalling was blocked by ERK inhibition. Consistent with this observation, cAMP elevation in HUVECs produced a transient yet robust activation of ERK, and subsequent phosphorylation of transcription factor C/EBP beta, both of which were resistant to PKA inhibition. However, siRNA depletion and immunoblotting experiments revealed that neither Epac1 nor Epac2 contributed to the PKA-independent activation of ERK1,2 observed following cAMP elevation. Together, these observations suggest that while SOCS-3 induction and subsequent inhibition of cytokine-mediated phosphorylation of ERK1,2 and STAT3 in response to cAMP require Epac1 and a transient PKA-independent activation of the ERK pathway, these two events are controlled by distinct mechanisms. In addition, it reveals a novel Epac-dependent mechanism by which cAMP can specifically inhibit ERK in response to cytokine receptor activation.

    Original languageEnglish
    Pages (from-to)1706-1715
    Number of pages10
    JournalCellular Signalling
    Volume21
    Issue number11
    DOIs
    Publication statusPublished - Nov 2009

    Keywords

    • CCAAT-Enhancer-Binding Protein-beta
    • Cells, Cultured
    • Cyclic AMP
    • Cyclic AMP-Dependent Protein Kinases
    • Cytokines
    • Endothelial Cells
    • Extracellular Signal-Regulated MAP Kinases
    • Gene Knockdown Techniques
    • Guanine Nucleotide Exchange Factors
    • Humans
    • Interleukin-6
    • Interleukin-6 Receptor alpha Subunit
    • Leptin
    • Phosphorylation
    • RNA, Small Interfering
    • STAT3 Transcription Factor
    • Signal Transduction
    • Suppressor of Cytokine Signaling Proteins

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