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

• Published in: The FASEB journal Vol. 18; no. 12; p. 1439
• Main Authors: Hegde, Subramanya, Pahne, Jenny, Smola-Hess, Sigrun
• Format: Journal Article
• Language: English
• Published: United States 01.09.2004
• Subjects: 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; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Receptors, CCR7; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects
• ISSN: 1530-6860

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.