The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62.
ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, has been shown to modulate the immune system through subversion of signal transduction pathways operating in various immune system cells. With respect to human bone marrow-derived mast cells (BMMCs), ES-62 was previously shown to inhibit FcϵRI-mediated mast cell functional responses such as degranulation and pro-inflammatory cytokine release through a mechanism involving the degradation of PKC-α. At the same time, it was noted that the worm product was able to degrade certain other PKC isoforms but the significance of this was uncertain. In this study, we have employed PKC isoform KO mice to investigate the role of PKC-α, -β -ϵ, and -θ in mouse BMMCs in order to establish their involvement in mast cell-mediated responses and also, if their absence impacts on ES-62's activity. The data obtained support that in response to antigen cross-linking of IgE bound to FcϵRI, pro-inflammatory cytokine release is controlled in part by a partnership between one conventional and one novel isoform with PKC-α and -θ acting as positive regulators of IL-6 and TNF-α production, while PKC-β and ϵ act as negative regulators of such cytokines. Furthermore, ES-62 appears to target certain other PKC isoforms in addition to PKC-α to inhibit cytokine release and this may enable it to more efficiently inhibit mast cell responses.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
Kara S
KS
Bell
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
Lamyaa
L
Al-Riyami
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
Felicity E
FE
Lumb
School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Graham J
GJ
Britton
School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Alastair W
AW
Poole
School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Christopher M
CM
Williams
The Biotechnology Centre of Oslo, University of Oslo, Oslo 0349, Norway.
Ursula
U
Braun
The Biotechnology Centre of Oslo, University of Oslo, Oslo 0349, Norway.
Michael
M
Leitges
Centre for Immunobiology, Glasgow Biomedical Research Centre, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
Margaret M
MM
Harnett
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address: w.harnett@strath.ac.uk.
William
W
Harnett
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015801:Helminth Proteins / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology*; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D064546:Protein Kinase C beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000099221:Protein Kinase C zeta
D015801:Helminth Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta; C435884:ES-62 protein, Acanthocheilonema viteae
ES-62; Immunomodulation; Mast cell; PKC; Signal transduction