Abstract 4861: Pharmacological reversal of caffeine-mediated phagocytic suppression

Abstract

Abstract Caffeine's mechanism of action on immune cells has been an issue of debate for some time. Previous studies suggest caffeine inhibits cyclic AMP (cAMP)-phosphodiesterase, resulting in increased cAMP levels, increased protein kinase A (PKA) activation, and subsequently a decreased pro-inflammatory response. Caffeine is also an antagonist of adenosine receptors, resulting in delayed resolution of inflammation. If the primary effect of caffeine in macrophages was to antagonize adenosine receptors, we would expect caffeine to stimulate phagocytosis. We treated human macrophages with varying concentrations of caffeine (0 - 13mM) and measured their phagocytic ability to engulf fluorescent microspheres. Engulfment rates were measured by flow cytometry. Our results indicate that caffeine suppresses phagocytosis by 22% at physiological concentrations (35 uM- 750uM). At supraphysiological (4-13 mM) levels of caffeine, however, there is no significant decrease in phagocytosis. We wanted to find out if this suppressive effect at physiological concentrations could be blocked with a PKA inhibitor. We tested this by treating the cells with a PKA inhibitor at each of the different caffeine concentrations previously used. Initial results indicate that phagocytosis increased up to 27% in macrophages treated with PKA and caffeine compared to caffeine treated and control cells.These results need further validation but, initial results suggest inhibition of PKA results in increased engulfment, and indicate that the suppressive effects of caffeine on macrophage phagocytosis can be reversed with the treatment of PKA inhibitor suppression can be reversed. Macrophages are highly involved in regulation of inflammation and dysregulation has been implicated in a number of diseases, including cancer. These results suggest further potential for the therapeutic applications of caffeine, its analogs, and PKA inhibitors for the control of inflammation. Citation Format: Ryan Steck, Spencer Hill, Richard A. Robison, Kim L. O'Neill. Pharmacological reversal of caffeine-mediated phagocytic suppression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4861. doi:10.1158/1538-7445.AM2014-4861