Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression

FASEB J. 2004 Sep;18(12):1439-41. doi: 10.1096/fj.03-0969fje. Epub 2004 Jul 9.


Interleukin-6 (IL-6) is produced during bacterial and viral infections and by various malignant tumors. Here, we describe novel immunosuppressive properties of IL-6 in dendritic cells (DC). In the presence of GM-CSF, IL-4, and a maturation stimulus, IL-6 skewed monocyte differentiation into phenotypically mature but functionally impaired DC. In DC matured with the toll-like receptor (TLR)4 stimulus lipopolysaccharide (LPS) or other pro-inflammatory stimuli, IL-6 inhibited CCR7 chemokine receptor up-regulation. As demonstrated for LPS-stimulated DC, IL-6 impaired chemotaxis to CCR7-activating chemokines required for recruiting DC to lymphoid tissues in vivo. Moreover, IL-6 inhibited production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma inducible protein-10 (IP-10) in DC, and DC-driven allogeneic T cell proliferation in mixed lymphocyte reactions. CCR7 expression was blocked at the transcriptional level. IL-6 led to inhibition of nuclear factor-kappaB (NF-kappaB) binding activity, regulating CCR7 transcription. Neutralization experiments revealed that autocrine IL-10 partially contributed to CCR7 suppression in IL-6-treated DC. Thus IL-6, a cytokine once labeled as "pro-inflammatory" can mediate immunosuppressive functions, which may involve induction of the classical "anti-inflammatory" cytokine IL-10. Because IL-6 is expressed in response to various pro-inflammatory stimuli in vivo, this mechanism may contribute to down-regulating the immune response initiated by pathogens, in persistent infections or tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemotaxis, Leukocyte / drug effects
  • Cytokines / biosynthesis
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology
  • Interleukin-10 / immunology
  • Interleukin-10 / pharmacology
  • Interleukin-6 / immunology*
  • Interleukin-6 / pharmacology
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR7
  • Receptors, Chemokine / biosynthesis
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CCR7 protein, human
  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger
  • Receptors, CCR7
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • p38 Mitogen-Activated Protein Kinases