Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes

J Leukoc Biol. 2020 Mar;107(3):497-508. doi: 10.1002/JLB.4VMA0318-138R. Epub 2019 Apr 1.


Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-α, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.

Keywords: Tacrolimus; antifungal response; cyclosporine A; pattern recognition receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / metabolism*
  • Aspergillus fumigatus / drug effects
  • Base Sequence
  • Binding Sites
  • C-Reactive Protein / metabolism*
  • Calcineurin Inhibitors / pharmacology*
  • Chemokines / metabolism
  • Cyclosporine / pharmacology
  • Humans
  • Interleukin-10 / metabolism
  • Mice
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • NFATC Transcription Factors / metabolism*
  • Protein Transport / drug effects
  • Sequence Homology, Amino Acid
  • Serum Amyloid P-Component / metabolism*
  • Signal Transduction / drug effects
  • THP-1 Cells
  • Tumor Necrosis Factor-alpha / metabolism


  • Antifungal Agents
  • Calcineurin Inhibitors
  • Chemokines
  • NFATC Transcription Factors
  • Serum Amyloid P-Component
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • PTX3 protein
  • Cyclosporine
  • C-Reactive Protein