Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells

Abstract

We analyzed interleukin (IL) 12 and IL-23 production by monocyte-derived dendritic cells (mono-DCs). Mycobacterium tuberculosis H37Rv and zymosan preferentially induced IL-23. IL-23 but not IL-12 was efficiently induced by the combination of nucleotide-binding oligodimerization domain and Toll-like receptor (TLR) 2 ligands, which mimics activation by M. tuberculosis, or by the human dectin-1 ligand beta-glucan alone or in combination with TLR2 ligands, mimicking induction by zymosan. TLR2 ligands inhibited IL-12 and increased IL-23 production. DC priming with interferon (IFN) gamma strongly increased IL-12 production, but was not required for IL-23 production and inhibited IL-23 production induced by beta-glucan. The pattern of IL-12 and IL-23 induction was reflected in accumulation of the IL-12p35 and IL-23p19 transcripts, respectively, but not IL-12/23p40. Although IL-23, transforming growth factor beta, and IL-6 contained in the supernatants of activated mono-DCs played a role in the induction of IL-17 by human CD4(+) T cells, IL-1beta, in combination with one or more of those factors, was required for IL-17 production, and its production determined the differential ability of the stimuli used to elicit mono-DCs to produce soluble factors directing IL-17 production. Thus, the differential ability of pathogens to induce antigen-presenting cells to produce cytokines regulates the immune response to infection

Notch- and Transducin-like Enhancer of Split (TLE)-dependent Histone Deacetylation Explain Interleukin 12 (IL-12) p70 Inhibition by Zymosan

“…At first glance, this may be explained because, unlike TLR2, TLR4 ligands activate the MyD88 and the TIR domain-containing adapter-inducing interferon-␤ routes and trigger both the NF-B pathway and the type I IFN autocrine-paracrine loop. However, this does not explain why TLR2 ligands may behave as negative modulators of IL-12 p70 production (7,9) nor the molecular mechanisms underlying the distinct patterns of IL-23/IL-12 p70 response. Whereas LPS induces both cytokines, Mycobacterium tuberculosis (7) and zymosan, an extract of the cell wall of Saccharomyces cerevisiae mainly composed of ␤-glucans that is recognized by at least the C-type lectin receptor dectin-1 (10) and TLR2 (11,12), induce IL-23 and a low amount of IL-12 p70 (12)(13)(14)(15).…”

“…il12/23b regulation depends on NF-B activation (3), whereas the transcriptional regulation of il12a also requires a type I interferon autocrine-paracrine loop involving interferon regulatory factors (IRF)-1, IRF-3, and IRF-8/ICSBP (3)(4)(5)(6). Stimulation of Toll-like receptor (TLR) 3 -4 induces an IL-12/IL-23 balance different from that elicited through the TLR2 and C-type lectin routes (7,8). At first glance, this may be explained because, unlike TLR2, TLR4 ligands activate the MyD88 and the TIR domain-containing adapter-inducing interferon-␤ routes and trigger both the NF-B pathway and the type I IFN autocrine-paracrine loop.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…131 Dectin-1 is shown to collaborate with TLR2, 4, 5, 7 or 9 to synergistically influence the secretion of many cytokines (inducing IL-23, while repressing IL-12). 132,133 In human PBMCs, Dectin-1/TLR2 pathway was able to amplify MRinduced IL-17 production, a vital cytokine upon C. albicans stimulus. This finding provides an evidence for the interaction between C-type lectin receptors and TLRs.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…IL-23 production by DCs is known to be an important driver of the Th17 response. 69,70 Interestingly, like these opportunistic fungi, the mutant H. capsulatum yeast form (Dags1) resulted in an increased production of IL-23. After blocking dectin-1 receptors with laminarin, the interleukin response was not observed, suggesting that dectin-1 receptors were involved in the mechanism.…”