CD40 ligand-triggered human dendritic cells mount interleukin-23 responses that are further enhanced by danger signals.
Interleukin (IL)-23 is a heterodimeric cytokine composed of the IL-23-specific subunit p19 and the p40 subunit which also constitutes part of IL-12. IL-23 propagates development of Th17 cells, a novel T cell subset which produces IL-17 but no interferon-gamma or IL-4. For both, IL-23 and IL-23-driven IL-17, a crucial role in autoimmune diseases such as experimental autoimmune encephalomyelitis, collagen-induced arthritis, and colitis is well accepted. Recent studies indicate that there is also a role for IL-23 and IL-17 in tumorigenesis, promoting tumor growth and vascularization, and affecting tumor incidence. We show that human CD14(+) peripheral blood monocyte-derived dendritic cells (DC), as used for clinical applications in anti-tumor immunization strategies, produce high amounts of IL-23. CD40-triggering of immature and mature DC but not of primary monocytes induced a rapid expression of high levels of IL-23, free p40, and minor levels of IL-12. Upon stimulation of DC subsets with a variety of different danger signals such as single stranded and double stranded RNA, bacterial components or viral infections, IL-23 expression pattern was analyzed. Interestingly, co-stimulation with CD40L enabled IL-23 expression by DC subsets towards danger signals to which they have been unresponsive upon single stimulation. Furthermore, we detected two novel splice variants of the IL-23-specific subunit p19 that could be associated with the regulation of IL-23 expression. Data presented here might have an impact on DC-based cancer vaccination strategies and contribute to a better understanding of the complex regulation of the heterodimeric cytokine IL-23.
Sender
Linda Y
LY
Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
Gibbert
Kathrin
K
Suezer
Yasemin
Y
Radeke
Heinfried H
HH
Kalinke
Ulrich
U
Waibler
Zoe
Z
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D023201:CD40 Ligand / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D051192:Receptors, Pattern Recognition / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D051192:Receptors, Pattern Recognition; D023201:CD40 Ligand