Thesis

The role of individual protein kinase C isoforms in mast cell function and their targeting by the immunomodulatory helminth product, ES-62

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Awarding institution
  • University of Strathclyde
Date of award
  • 2013
Thesis identifier
  • T13700
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Abstract
  • ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, is immunomodulatory via subversion of signal transduction pathways operating in various immune system cells. With respect to human bone-marrow derived mast cells (BMMC), ES-62 has previously been shown to inhibit FcεRI-mediated degranulation by forming a complex with TLR4 to sequester PKC-α away from the plasma membrane, resulting in its degradation. An intriguing additional finding was that ES-62 reduced levels of other PKC isoforms, namely PKC-β, -δ, -ι and -ζ. This project is concerned with establishing if PKC isoforms targeted by ES-62 are critical for BMMC functional responses and if so, whether the absence of any such isoform impacts on ES-62-mediated inhibition of mast cell responses. To establish the role, which each PKC isoform plays in mast cell function, PKC isoform knockout (KO) mice were employed. Simultaneously other types of immune system cell, namely macrophages and dendritic cells were explored, to establish whether any effects observed are mast cell-specific. The data obtained with mast cells indicate that control of pro-inflammatory cytokine production is possibly mediated by a partnership between one conventional and one novel isoform with PKC-α and more importantly, PKC-θ, acting as positive regulators of IL-6 and TNF-α production while on the other hand PKC-β and -ε act as negative regulators of IL-6 production. Although the loss of any one PKC isoform had no clear detrimental effects on ES-62 activity, the absence of PKC-θ may possibly dampen the nematode product's modulatory ability. The utilization of PKC-α, -β and -θ is specific for BMMC functional responses in comparison to macrophages whereby only PKC-ε was VII revealed as a positive regulator of IL-6. Interestingly however, PKC-α also appears to be an ES-62 target in macrophages. With respect to dendritic cells, in contrast to antigen-stimulated BMMC, PKC-α negatively regulates LPS-induced IL-6 and TNF-α.
Resource Type
DOI
Date Created
  • 2013
Former identifier
  • 1031348

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