Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression.
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.
Hegde
Subramanya
S
Institute of Virology, University of Cologne, Cologne, Germany.
Pahne
Jenny
J
Smola-Hess
Sigrun
S
D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515370:CCR7 protein, human; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases