Abstract
Background:
Serum caffeine concentrations >20 μg/ml (100 μmol/l) in infants treated for apnea of prematurity increases TNF-α and decreases IL-10, changes that perhaps are linked to comorbidities. We hypothesize that this proinflammatory cytokine profile may be linked to differential binding of caffeine to adenosine receptor subtypes (AR), inhibition of phosphodiesterases (PDEs), and modulation of toll-like receptors (TLR).
Methods:
Lipopolysaccharide-activated cord blood monocytes (CBM) from 19 infants were exposed to caffeine (0–200 μmol/l) with or without previous exposure to A1R, A3R, or PDE IV antagonists to determine changes in dose–response curves. Cytokines levels (enzyme-linked immunosorbent assay (ELISA)), intracellular cyclic adenosine monophosphate (cAMP) accumulation (enzyme immunoassay (EIA)), and TLR gene expression (real time qRT PCR) were measured.
Results:
Caffeine at ≤100 μmol/l decreased TNF-α levels (~25%, P = 0.01) and cAMP. All caffeine concentrations decreased IL-10 levels (17–35%, P < 0.01). A1R, A3R, and PDE blockades decreased TNF-α (31, 21, and 88%, P ≤ 0.01), but not IL-10. Caffeine further decreased TNF-α following A3R and PDE blockades. Caffeine concentrations directly correlated to TLR4 gene expression (r = 0.84; P < 0.001).
Conclusion:
Neither A3R, nor PDE blockades are involved in caffeine’s modulation of cytokine release by CBM at any concentration. Besides A1R blockade, caffeine’s upregulation of TLR4 may promote inflammation at high concentrations.
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Acknowledgements
We thank Ariel Mason and Veronica Bostic for their administrative assistance as well as the obstetric team at Johns Hopkins Hospital for their support.
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Chavez-Valdez, R., Ahlawat, R., Wills-Karp, M. et al. Mechanisms of modulation of cytokine release by human cord blood monocytes exposed to high concentrations of caffeine. Pediatr Res 80, 101–109 (2016). https://doi.org/10.1038/pr.2016.50
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DOI: https://doi.org/10.1038/pr.2016.50
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