Increased production of pro-inflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand.
BACKGROUND
Various microbial, inflammatory and immune signals regulate the activation of dendritic cells (DC), determining their ability to interact with naïve T cells and to produce cytokines that direct T cell development. In particular, CD40L and IL-1 cooperatively activate DC to secrete high levels of IL-12. The immuno-stimulatory capacity of such DC is otherwise not well-defined prompting further characterization of the effects of IL-1 and family members on DC activation in comparison with other pro-inflammatory stimuli.


RESULTS
Human DC co-activated in vitro by CD40L and IL-1beta expressed numerous cytokine genes including IL-12beta, IL-23 p19, IL-1beta, IL-1alpha, IL-1Ra, IL-10, IL-6, IL-18 and IFN-gamma. These DC produced high levels of IL-12 protein and appeared capable of producing IFN-gamma. Potent CD4+ and CD8+ T cell-stimulatory properties were acquired by DC under conditions that also induced IL-12. Notably, these DC induced rapid differentiation of fluMP-specific CD8+ T cells. Molecules related to IL-1beta, like IL-1alpha, co-induced IL-12 secretion whereas IL-18 did not. Conversely, the inhibitor IL-1Ra, produced endogenously by DC curtailed IL-12 production in response to CD40L.


CONCLUSIONS
IL-1 and IL-1Ra play a biologically-relevant role in the positive and negative regulation of DC activation. In conjunction with CD40L, IL-1 sends a powerful activation signal to DC that could be distinguished from other modes of activation. This signal enables the production of pro-inflammatory cytokines by DC, and enhances the differentiation of naïve T cells into effectors of type-1 cellular immune responses.
Wesa
Amy
A
Cancer Biology Program and Department of Immunology and Microbiology, Barbara Ann Karmanos Cancer Institute of Wayne State University, Detroit, USA. wesaa@karmanos.org
Galy
Anne
A
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D019013:CD40 Antigens; D016207:Cytokines; C508840:IL23A protein, human; D007375:Interleukin-1; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D007378:Interleukins; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma