Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer

Kaliński, Paweł; Vieira, Pedro L.; Schuitemaker, Joost H. N.; Jong, Esther C. de; Kapsenberg, Martien L.

doi:10.1182/blood.v97.11.3466

Cited by 338 publications

(276 citation statements)

References 40 publications

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“…Interestingly, it has been shown previously that stimulation of DC with TNF-a and PGE 2 leads to a selective induction of p40 transcription and secretion while inhibiting p70 secretion. 2 The responsible mechanisms may be unique to IL-12 in that p40 can be secreted in several ways, as p40 monomer, p40-p40 homodimer, IL-12p70 and, if p40 is bound to p19, IL-23. This phenomenon has yet to be elucidated, but may involve the different kinetics of transcription of p40 and p35, different kinetics in the translation and post-translational modification, as well as the yet unknown influence of p19 as a competing binding partner for p40.…”

Section: Resultsmentioning

confidence: 99%

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Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype

et al. 2004

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Interleukin-12 (IL-12), a heterodimeric cytokine, is important in the generation of a Th1-biased immune response. Several polymorphisms have been described in IL12B, the gene encoding the p40 subunit of IL-12. A bi-allelic polymorphism within the IL12B promoter region has been reported to show association with diseases as diverse as severe childhood asthma and fatal cerebral malaria. In order to define the molecular basis for these disease associations, we investigated the secretion of IL-12 by human monocyte-derived dendritic cells. Homozygotes for the IL12B promoter polymorphism showed a 10-fold difference in median p70 secretion in response to CD40 ligation. Remarkably, this difference resulted from the inability of most allele 1 homozygotes to secrete heterodimeric IL-12. In contrast, most of the donors homozygous for allele 2 had detectable secretion. These findings are important for the understanding of the highly complex regulation of IL-12 secretion, and its consequent impact on disease susceptibility, in humans.

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Section: Resultsmentioning

confidence: 99%

“…1 These chains are encoded by genes on different chromosomes and their production can be regulated independently. 2,3 IL-12 is produced by a number of cell types, including macrophages, neutrophilic granulocytes and dendritic cells (DCs). DCs may be the most important source of IL-12.…”

Section: Introductionmentioning

confidence: 99%

Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype

et al. 2004

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“…Previous reports have shown that the Th2-cell promoting mediator PGE 2 induces the secretion of IL-12p40 in DCs thereby inhibiting the production of the Th1-cell driving cytokine IL12p70 [16][17][18]. It has been proposed that blocking or washing out IL-12p70 production is sufficient to drive the differentiation of Th2-cell responses by the so-called default or exhaustion pathway [64,65].…”

Section: Discussionmentioning

confidence: 99%

“…These include costimulatory molecules such as OX40 [12], ICOS-L [13], the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the factors that induce such Th2-instructing DC.…”

Section: Introductionmentioning

confidence: 99%

“…Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the factors that induce such Th2-instructing DC.…”

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Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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Isolation and Generation of Human Dendritic Cells

2012

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Dendritic cells are highly specialized antigen-presenting cells (APC), which may be isolated or generated from human blood mononuclear cells. Although mature blood dendritic cells normally represent ~0.2% of human blood mononuclear cells, their frequency can be greatly increased using the cell enrichment methods described in this unit. More highly purified dendritic cell preparations can be obtained from these populations by sorting of fluorescence-labeled cells. Alternatively, dendritic cells can be generated from monocytes by culture with the appropriate cytokines, as described here. In addition, a negative selection approach is provided that may be employed to generate cell preparations that have been depleted of dendritic cells to be used for comparison in functional studies.

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Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer

Cited by 338 publications

References 40 publications

Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype

Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Isolation and Generation of Human Dendritic Cells

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