Studies on the purported role of lipid methylation in mast cell activation

Benyon, Robert Christopher (1986) Studies on the purported role of lipid methylation in mast cell activation. University of Southampton, Doctoral Thesis.

Abstract

Increased N-methylation of phosphatidylethanolamine (PE) has previously been reported to be a consequence of IgE-dependent stimulation of mast cells and basophils. It has been proposed that such lipid conversions may facilitate receptor-mediated calcium accumulation, adenylate cyclase activation and phosphoinositide metabolism. My studies demonstrate that the methylation inhibitors 3-deazaadenosine and adenosine are effective inhibitors of IgE dependent histamine secretion from rat peritoneal and human lung mast cells. These findings are consistent with the hypothesis that methylation reactions are involved in stimulus-secretion coupling. However, the proposed functions of PE methylation are questioned by my findings that, in these cells, IgE-dependent activation was not associated with increased radiolabelling of PE in cells prelabelled with [³H-methyl] donor. In investigating alternative mechanisms of action of the methylation inhibitors used, it was observed that concentrations of 3-deazaadenosine which effectively inhibited PE methylation in unstimulated cells increased both basal and anti-IgE-stimulated levels of cyclic AMP. These findings argue against the suggested involvement of PE methylation in the activation of mast cell adenylate cyclase. Although agents which elevate mast cell cyclic AMP levels generally inhibit IgE-dependent histamine secretion, 3-deazaadenosine-induced increases in cyclic AMP were small and probably did not account for its effects on secretion. In summary therefore, IgE-dependent activation of rat and human mast cells is not associated with increased PE methylation, although pharmacological studies indicate that methylation of as yet unidentified substrates might be involved in the mechanism of histamine secretion. (D75609/87)

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