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

Müller-Berghaus, Jan; Kern, Katharina; Paschen, Annette; Nguyen, Xuan Duc; Klüter, Harald; Morahan, Grant; Schadendorf, Dirk

doi:10.1038/sj.gene.6364102

Cited by 49 publications

(57 citation statements)

References 21 publications

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“…In general, there is a disagreement about the effect of IL12Bpro polymorphism on the inducible IL-12p40 production. The investigations of Müller-Berghaus et al [24] showed that there were no significant differences in IL-12p40 production between IL12Bpro-1 homozygotes, heterozygotes and 2.2 homozygotes, realized by monocyte-derived dendritic cells after stimulation with CD40L. By contrast, Morahan et al [9] revealed that heterozygosity in the IL12B promoter sequence reduced IL-12p40 mRNA synthesis in PBMC from asthmatic children.…”

Section: Discussionmentioning

confidence: 91%

“…The sequence of the primer specific for the CTCTAA allele, marked as IL12Bpro-1 was 5'-TGT CTC CGA GAG AGG CTC TAA-3'; and that for the GC allele marked as IL12Bpro-2 was 5'-TGT CTC CGA GAG AGG GCT GT-3'. The generic 3' primer used for the amplification reactions was 5'-TGG AGG AAG TGG TTC TCG TAC-3' [24]. The cycling parameters were: an initial denaturation step of 15 min at 95ºC, 30 cycles of 30 sec at 95ºC, 30 sec at 65ºC, and 30 sec at 72ºC, with a final extension step of 7 min at 72ºC.…”

Section: Genomic Dna Isolation and Genotypingmentioning

confidence: 99%

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The influence of JNK and P38 MAPK inhibition on IL-12P40 and IL-23 production depending on IL12B promoter polymorphism

Dobreva

Stanilova

Miteva

2009

Cellular and Molecular Biology Letters

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Abstract:The interleukin-12p40 gene (IL12B) encodes the p40 polypeptide chain, which, together with p19, composes IL-23. A bi-allelic promoter polymorphism (IL12Bpro) located at -2703 bp of the transcription initiation site has been reported to show associations with IL-12p40 production. To elucidate the dependence of IL-12p40 and IL-23 production on IL12Bpro polymorphism in relation to MAPK signal transduction pathways, we examined the effect of JNK and p38 inhibition on the secretion of these cytokines by stimulated peripheral blood mononuclear cells (PBMC) from healthy donors with 1.1 and 1.2/2.2 IL12Bpro genotypes. Stimulation with LPS and C3bgp resulted in approximately equal IL-12p40 production from PBMC with the 1.1 and 1.2/2.2 genotypes. The inhibition of JNK and p38 before stimulation significantly upregulated IL-12p40 production by PBMC with the 1.1 genotype, but did not influence IL-12p40 production from PBMC with the 1.2/2.2 genotype. Cultures of PBMC with the 1.1 genotype produced significantly more IL-12p40 than PBMC with the 1.2/2.2 genotype after stimulation with PHA. Inhibition of p38 kinase upregulated p40 production only in cultures with the 1.1 genotype. Decreased IL-23 production was observed in C3bgp-stimulated cultures after the inhibition of p38 regardless of the genotype of the tested cells. We concluded that IL-12p40 and IL-23 expression, which is mediated by the p38 and JNK intracellular signaling pathways, is influenced by IL12Bpro polymorphism.

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Section: Discussionmentioning

confidence: 91%

Section: Genomic Dna Isolation and Genotypingmentioning

confidence: 99%

The influence of JNK and P38 MAPK inhibition on IL-12P40 and IL-23 production depending on IL12B promoter polymorphism

Dobreva

Stanilova

Miteva

2009

Cellular and Molecular Biology Letters

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“…We suppose that a reason for our contrary findings might be the different type of IL-12B expression in isolated monocytes and PBMC. Muller-Berghaus et al 20 recently reported the effect of IL-12Bpro on dendritic cell IL-12 production and considered that the effects of the IL-12Bpro alleles may vary according to cell type and stimulus. Moreover, our results indicated that the production of IL-12p40 strongly depends on the stimuli used.…”

Section: Resultsmentioning

confidence: 99%

Taq-I polymorphism in 3′UTR of the IL-12B and association with IL-12p40 production from human PBMC

Stanilova

Miteva

2005

Genes Immun

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A wide array of studies has demonstrated differences in genotype and allele frequencies of cytokine gene polymorphisms depending on ethnicity and race. In this study, the frequency of Taq-I polymorphism in 3 0 untranslated region of IL-12B was investigated in two Bulgarian ethnic groups-Bulgarians and Turkish minority. No significant differences of genotype and allele frequencies were observed between these groups. Genotype distribution in the total group of Bulgarian citizens was: AA (61%), CA (32%) and CC (7%), and the allele frequency of 16974 A allele was 0.77. We also evaluated whether this polymorphism affects IL-12p40 production from human PBMC after stimulation. We demonstrated that association between genotype and IL12p40 production by stimulated PBMC depends on the stimuli used. Our results indicated a significantly decreased IL-12 p40 secretion for the following order of genotypes: AA4CA4CC, after stimulation of PBMC with C3-binding glycoprotein (C3bgp) in contrast to lipopolysaccharide, phytohaemagglutinin and pokeweed mitogen.

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“…A 4-bp insertion in the promoter region of IL-12B (IL-12Bpro; rs17860508) has been shown to decrease the amount of IL-12p70 secreted by human monocyte-derived dendritic cells in vitro. 7 A further polymorphism present within the 3 0 UTR of the IL-12B gene (rs3212227), reflecting an A to C nucleotide substitution at position 1188, has been associated with various autoimmune diseases including type 1 diabetes, 8 multiple sclerosis 9 and psoriasis. 10 The IL-12 p40 subunit can also form heterodimers with p19 resulting in formation of IL-23.…”

Section: Interleukin (Il)-17a Is the Prototypic Cytokine Produced By Cd4mentioning

confidence: 99%

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

et al. 2011

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The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4 þ T-helper 17 (Th 17 ) cells, whereas IL-12 negates IL-17A production by promoting Th 1 -cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml --1 vs 176.11 ± 277.32 pg ml --1 ; P ¼ 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.

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

Cited by 49 publications

References 21 publications

The influence of JNK and P38 MAPK inhibition on IL-12P40 and IL-23 production depending on IL12B promoter polymorphism

The influence of JNK and P38 MAPK inhibition on IL-12P40 and IL-23 production depending on IL12B promoter polymorphism

Taq-I polymorphism in 3′UTR of the IL-12B and association with IL-12p40 production from human PBMC

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

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