Caffeine Has Different Immunomodulatory Effect on the Cytokine Expression and NLRP3 Inflammasome Function in Various Human Macrophage Subpopulations

Nutrients. 2021 Jul 14;13(7):2409. doi: 10.3390/nu13072409.


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.

Keywords: NLRP3 inflammasome; caffeine; cytokines; inflammation; macrophages; signaling.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Caffeine / pharmacology*
  • Cells, Cultured
  • Cytokines / metabolism*
  • Humans
  • Immunologic Factors / pharmacology*
  • Inflammasomes / metabolism*
  • Inflammation Mediators / metabolism*
  • Macrophage Activation / drug effects*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phenotype
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Adenosine A2B / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism


  • ADORA2A protein, human
  • ADORA2B protein, human
  • Cytokines
  • Immunologic Factors
  • Inflammasomes
  • Inflammation Mediators
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Caffeine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases