title: Mechanisms of modulation of cytokine release by human cord blood monocytes exposed to high concentrations of caffeine.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Johns Hopkins University-School of Medicine, Baltimore, Maryland.
authors.forename: Raul
authors.initials: R
authors.lastname: Chavez-Valdez
authors.affiliation: Department of Pediatrics, Division of Pediatric Gastroenterology, North Shore LIJ Health System, Lake Success, New York.
authors.forename: Rajni
authors.initials: R
authors.lastname: Ahlawat
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.affiliation: Department of Pediatrics, Division of Neonatology, Johns Hopkins University-School of Medicine, Baltimore, Maryland.
authors.forename: Estelle B
authors.initials: EB
authors.lastname: Gauda
mesh_terms: D001034:Apgar Score; D001049:Apnea / Q000097:blood / Q000188:drug therapy*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D015897:Comorbidity; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005312:Fetal Blood / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D009000:Monocytes / Q000187:drug effects*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000697:Central Nervous System Stimulants; D016207:Cytokines; C508609:IL10 protein, human; D008070:Lipopolysaccharides; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002110:Caffeine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases