Abstract
Besides its well-known psychoactive effects, caffeine has a broad range of actions. It regulates several physiological mechanisms as well as modulates both native and adaptive immune responses by various ways. Although caffeine is assumed to be a negative regulator of inflammation, the effect on the secretion of pro- and anti-inflammatory cytokines is highly controversial. Macrophages are major mediators of inflammatory responses; however, the various subpopulations develop different effects ranging from the initiation to the resolution of inflammation. Here we report a comparative analysis of the effect of caffeine on two subpopulations of human monocyte-derived macrophages differentiated in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in M-MΦs and GM-MΦs, respectively. We showed that although TNF-α secretion was downregulated in both LPS-activated MΦ subtypes by caffeine, the secretion of IL-8, IL-6, and IL-1β as well as the expression of Nod-like receptors was enhanced in M-MΦs, while it did not change in GM-MΦs. We showed that caffeine (1) altered adenosine receptor expression, (2) changed Akt/AMPK/mTOR signaling pathways, and (3) inhibited STAT1/IL-10 signaling axis in M-MΦs. We hypothesized that these alterations play an important modulatory role in the upregulation of NLRP3 inflammasome-mediated IL-1β secretion in LPS-activated M-MΦs following caffeine treatment.
Highlights
Caffeine is a naturally occurring methylxanthine derivative that, as an antagonist of adenosine receptors, has impact on a wide range of physiological processes including the function of the nervous, cardiovascular, and immune systems
Our results indicate that caffeine drives cell specific immunomodulatory effects. These results showed that caffeine modulates several factors that may intervene with NLRP3 inflammasome activation, resulting in an enhanced and prolonged IL-1β secretion by the LPS-activated M-MΦs
As upon caffeine treatNutrients 2021, 13,ment, LPS-activated M-MΦs showed prolonged IL-1β secretion and significantly enhanced expression of NLRP3, we aimed to study whether the expression of the components of NLRP3 inflammasome is affected by caffeine pre-treatment
Summary
Caffeine is a naturally occurring methylxanthine derivative that, as an antagonist of adenosine receptors, has impact on a wide range of physiological processes including the function of the nervous, cardiovascular, and immune systems. Caffeine is used to treat apnea of prematurity in preterm newborn infants, and it has been found to reduce bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants, by reducing pulmonary inflammation, including IL-6 and TNF-α secretion [4,5]. Caffeine is most often reported as a negative regulator of inflammatory responses due to its inhibitory effect on the secretion of TNF-α pro-inflammatory cytokine [6,7]. Its effect on the secretion of other inflammatory cytokines, such as IL-6, IL-8, and IL-1β, is highly controversial, probably due to the different conditions, model systems, and cell types used in the studies [8]
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