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Novel immunosuppressive properties of interleukin‐6 in dendritic cells: inhibition of NF‐κB binding activity and CCR7 expression
Author(s) -
Hegde Subramanya,
Pahne Jenny,
SmolaHess Sigrun
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0969fje
Subject(s) - c c chemokine receptor type 7 , chemokine , cytokine , autocrine signalling , tumor necrosis factor alpha , microbiology and biotechnology , immune system , biology , interleukin , monocyte , immunology , chemistry , cancer research , receptor , chemokine receptor , biochemistry
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‐α (TNF‐α) and interferon‐γ 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‐κB (NF‐κB) 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.