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Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis.

Plantinga TS, Fransen J, Takahashi N, Stienstra R, van Riel PL, van den Berg WB, Netea MG, Joosten LA - Arthritis Res. Ther. (2010)

Bottom Line: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients.However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, P,O, Box 9101, 6500 HB Nijmegen, The Netherlands. t.plantinga@aig.umcn.nl

ABSTRACT

Introduction: Dectin-1, a pattern recognition receptor expressed by the innate immune system, is known to be a major receptor inducing Th17-type adaptive immune responses that have been demonstrated to mediate autoimmunity. In this study, dectin-1 mRNA and protein expression, as well as the recently characterized DECTIN-1 Y238X early stop codon polymorphism, were studied in relation to rheumatoid arthritis (RA) susceptibility and severity.

Methods: Dectin-1 mRNA expression was measured in synovial tissue specimens of RA, osteoarthritis (OA), and nonrheumatic patients. Dectin-1 protein expression and localization were assessed in RA synovial tissue specimens. Macrophages from individuals with different DECTIN-1 genotypes were examined for differences in cytokine responses on dectin-1 stimulation. Furthermore, clinical parameters of inflammation and bone destruction of 262 RA patients were correlated with the presence of the DECTIN-1 Y238X polymorphism.

Results: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients. Accordingly, dectin-1 protein expression in RA synovial tissue biopsies was moderate to high, especially on macrophage-like cells. Cytokine production capacity of macrophages bearing the DECTIN-1 Y238X polymorphism was demonstrated to be impaired on dectin-1 stimulation. However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.

Conclusions: Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

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Cytokine production capacity of TNF-α (a) and IL-1β (b) after stimulation of monocyte derived macrophages during 24 hours with β-glucan, Pam3Cys, or β-glucan/Pam3Cys. Cells were obtained from individuals with the wild-type (WT, n = 6), heterozygous (HET, n = 4), and homozygous (HOM, n = 4) for the DECTIN-1 Y238X polymorphism. Cytokine concentrations were determined with enzyme-linked immunosorbent assay (ELISA). Data are expressed as mean values ± SD, *P ≤ 0.05.
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Figure 3: Cytokine production capacity of TNF-α (a) and IL-1β (b) after stimulation of monocyte derived macrophages during 24 hours with β-glucan, Pam3Cys, or β-glucan/Pam3Cys. Cells were obtained from individuals with the wild-type (WT, n = 6), heterozygous (HET, n = 4), and homozygous (HOM, n = 4) for the DECTIN-1 Y238X polymorphism. Cytokine concentrations were determined with enzyme-linked immunosorbent assay (ELISA). Data are expressed as mean values ± SD, *P ≤ 0.05.

Mentions: Because especially macrophages are known to express dectin-1 in high amounts and are possibly involved in RA pathogenesis, we analyzed the functional consequences of the DECTIN-1 Y238X polymorphism for the inflammatory response of these cells with dectin-1 stimulation. Monocytes were differentiated into macrophages in vitro and were stimulated for 24 hours with β-glucan, the TLR2 agonist Pam3Cys, and both ligands simultaneously. After stimulation with β-glucan, cytokine measurements revealed a diminished TNF-α and IL-1β production capacity in cells from individuals homozygous for the Y238X polymorphism compared with cells from wild-type individuals. In cells from heterozygous individuals, these responses were intermediate. Moreover, the previously described synergy between dectin-1 and TLR2 induced responses [11,12] regarding TNF-α and IL-1β production was abolished in cells isolated from individuals with the polymorphism. The TLR2/dectin-1 synergism was reduced in cells isolated from heterozygous individuals and was completely absent in cells obtained from individuals homozygous for the Y238X polymorphism compared with the individuals bearing only the wild-type DECTIN-1 allele (Figure 3).


Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis.

Plantinga TS, Fransen J, Takahashi N, Stienstra R, van Riel PL, van den Berg WB, Netea MG, Joosten LA - Arthritis Res. Ther. (2010)

Cytokine production capacity of TNF-α (a) and IL-1β (b) after stimulation of monocyte derived macrophages during 24 hours with β-glucan, Pam3Cys, or β-glucan/Pam3Cys. Cells were obtained from individuals with the wild-type (WT, n = 6), heterozygous (HET, n = 4), and homozygous (HOM, n = 4) for the DECTIN-1 Y238X polymorphism. Cytokine concentrations were determined with enzyme-linked immunosorbent assay (ELISA). Data are expressed as mean values ± SD, *P ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875660&req=5

Figure 3: Cytokine production capacity of TNF-α (a) and IL-1β (b) after stimulation of monocyte derived macrophages during 24 hours with β-glucan, Pam3Cys, or β-glucan/Pam3Cys. Cells were obtained from individuals with the wild-type (WT, n = 6), heterozygous (HET, n = 4), and homozygous (HOM, n = 4) for the DECTIN-1 Y238X polymorphism. Cytokine concentrations were determined with enzyme-linked immunosorbent assay (ELISA). Data are expressed as mean values ± SD, *P ≤ 0.05.
Mentions: Because especially macrophages are known to express dectin-1 in high amounts and are possibly involved in RA pathogenesis, we analyzed the functional consequences of the DECTIN-1 Y238X polymorphism for the inflammatory response of these cells with dectin-1 stimulation. Monocytes were differentiated into macrophages in vitro and were stimulated for 24 hours with β-glucan, the TLR2 agonist Pam3Cys, and both ligands simultaneously. After stimulation with β-glucan, cytokine measurements revealed a diminished TNF-α and IL-1β production capacity in cells from individuals homozygous for the Y238X polymorphism compared with cells from wild-type individuals. In cells from heterozygous individuals, these responses were intermediate. Moreover, the previously described synergy between dectin-1 and TLR2 induced responses [11,12] regarding TNF-α and IL-1β production was abolished in cells isolated from individuals with the polymorphism. The TLR2/dectin-1 synergism was reduced in cells isolated from heterozygous individuals and was completely absent in cells obtained from individuals homozygous for the Y238X polymorphism compared with the individuals bearing only the wild-type DECTIN-1 allele (Figure 3).

Bottom Line: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients.However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, P,O, Box 9101, 6500 HB Nijmegen, The Netherlands. t.plantinga@aig.umcn.nl

ABSTRACT

Introduction: Dectin-1, a pattern recognition receptor expressed by the innate immune system, is known to be a major receptor inducing Th17-type adaptive immune responses that have been demonstrated to mediate autoimmunity. In this study, dectin-1 mRNA and protein expression, as well as the recently characterized DECTIN-1 Y238X early stop codon polymorphism, were studied in relation to rheumatoid arthritis (RA) susceptibility and severity.

Methods: Dectin-1 mRNA expression was measured in synovial tissue specimens of RA, osteoarthritis (OA), and nonrheumatic patients. Dectin-1 protein expression and localization were assessed in RA synovial tissue specimens. Macrophages from individuals with different DECTIN-1 genotypes were examined for differences in cytokine responses on dectin-1 stimulation. Furthermore, clinical parameters of inflammation and bone destruction of 262 RA patients were correlated with the presence of the DECTIN-1 Y238X polymorphism.

Results: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients. Accordingly, dectin-1 protein expression in RA synovial tissue biopsies was moderate to high, especially on macrophage-like cells. Cytokine production capacity of macrophages bearing the DECTIN-1 Y238X polymorphism was demonstrated to be impaired on dectin-1 stimulation. However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.

Conclusions: Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

Show MeSH
Related in: MedlinePlus