Abstract
Honey bee venom has been established to have significant effect in immunotherapy. In the present study, (Z)-11-eicosenol-a major constituent of bee venom, along with its derivations methyl cis-11-eicosenoate and cis-11-eicosenoic acid, were synthesised to investigate their immune stimulatory effect and possible use as vaccine adjuvants. Stimuli that prime and activate the immune system have exerted profound effects on immune cells, particularly macrophages; however, the effectiveness of bee venom constituents as immune stimulants has not yet been established. Here, the abilities of these compounds to act as pro-inflammatory stimuli were assessed, either alone or in combination with lipopolysaccharide (LPS), by examining the secretion of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 by THP-1 macrophages. The compounds clearly increased the levels of IL-1β and decreased IL-10, whereas a decrease in IL-6 levels suggested a complex mechanism of action. A more in-depth profile of macrophage behaviour was therefore obtained by comprehensive untargeted metabolic profiling of the cells using liquid chromatography mass spectrometry (LC-MS) to confirm the ability of the eicosanoids to trigger the immune system. The level of 358 polar and 315 non-polar metabolites were changed significantly (p < 0.05) by all treatments. The LPS-stimulated production of most of the inflammatory metabolite biomarkers in glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, purine, pyrimidine and fatty acids metabolism were significantly enhanced by all three compounds, and particularly by methyl cis-11-eicosenoate and cis-11-eicosenoic acid. These findings support the proposed actions of (Z)-11-eicosenol, methyl cis-11-eicosenoate and cis-11-eicosenoic acid as immune system stimulators.
Highlights
Adjuvants, in the context of vaccines, are described as substances capable of enhancing and modulating antigen-specific immune responses to improve vaccine efficacy [1]
The present study identifies the main effects of synthetic compounds related to 11-eicosanol, which is found in bee venom, in modulating macrophage behaviour
In agreement with previous findings [17,37], a stimulatory effect of LPS was confirmed in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells
Summary
In the context of vaccines, are described as substances capable of enhancing and modulating antigen-specific immune responses to improve vaccine efficacy [1]. The immune stimulating effects of adjuvants was first established with the addition of aluminium potassium sulphate or aluminium salts to human vaccines [2,3]. Several studies have suggested that adjuvants act by enhancing T and B cell responses, by stimulating innate immunity and by increasing the magnitude of the adaptive responses to the vaccine [4,5,6]. Adjuvants stimulate a strong and comprehensive immune response to antigen by mimicking natural defensive trigger molecules, such as endogenous immune-active substances (e.g., chemokines and cytokines) or other natural compounds (e.g., vitamin E and saponins) [3]
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