Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance

J Clin Invest. 2006 Apr;116(4):916-28. doi: 10.1172/JCI27203.


Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+ IL-12(p70)- IL-6low regulatory DCs and TGF-beta+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorescent Antibody Technique
  • Humans
  • Immune Tolerance*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism
  • Lectins, C-Type
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Spleen
  • Time Factors
  • Toll-Like Receptor 2 / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Yeasts / metabolism
  • Zymosan / administration & dosage
  • Zymosan / metabolism
  • Zymosan / pharmacology*


  • Cytokines
  • Interleukin-6
  • Lectins, C-Type
  • Lipopolysaccharides
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Toll-Like Receptor 2
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • dectin 1
  • Interleukin-10
  • Interleukin-12
  • Zymosan
  • Extracellular Signal-Regulated MAP Kinases