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Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines.

Badot V, Durez P, Van den Eynde BJ, Nzeusseu-Toukap A, Houssiau FA, Lauwerys BR - J. Cell. Mol. Med. (2011)

Bottom Line: We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion.In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade.In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.

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FLS and activated CD4 T cells produce two IL-7R α-chain isoforms. (A) IL-7R Western blots on protein extracts from FLS and PBMC, and IL-7R PCR on cDNA from duplicate TNF-α and IL-1β activated FLS (1), IL-2 and PHA activated CD4 T cells (2), antigen-activated CD8 T cell clones (3) and B-EBV cells (4). Arrows indicate the expected sizes of the membrane-bound IL-7R. (B) Sequencing of purified IL-7R PCR fragments indicates that FLS produce a full-length IL-7R α-chain and a truncated form of the IL-7R α-chain lacking exon 6 encoding the transmembrane domain, thereby resulting in a secreted form of the molecule.
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fig01: FLS and activated CD4 T cells produce two IL-7R α-chain isoforms. (A) IL-7R Western blots on protein extracts from FLS and PBMC, and IL-7R PCR on cDNA from duplicate TNF-α and IL-1β activated FLS (1), IL-2 and PHA activated CD4 T cells (2), antigen-activated CD8 T cell clones (3) and B-EBV cells (4). Arrows indicate the expected sizes of the membrane-bound IL-7R. (B) Sequencing of purified IL-7R PCR fragments indicates that FLS produce a full-length IL-7R α-chain and a truncated form of the IL-7R α-chain lacking exon 6 encoding the transmembrane domain, thereby resulting in a secreted form of the molecule.

Mentions: In our previous experiments, we demonstrated that RA patients have higher synovial IL-7R gene and protein expression as compared to osteoarthritis or lupus patients [12]. Moreover, we found that synovial overexpression of IL-7R in DMARD-resistant RA patients is associated with poor response to TNF blockade [6]. In these earlier experiments, anti IL-7R antibodies stained not only synovial mononuclear cells, but also synovial fibroblasts. Therefore, we wanted to further study the production and regulation of IL-7R by cultured FLS obtained from the joints of RA patients. Western blot and real-time qPCR experiments indicated that FLS express two isoforms of the molecule (Fig. 1A). Sequencing of the amplicons demonstrated that these isoforms correspond to the native IL-7R, and an alternatively spliced variant lacking exon 6 (transmembrane domain), which encodes a soluble form of the IL-7R (sIL-7R) (Fig. 1B).


Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines.

Badot V, Durez P, Van den Eynde BJ, Nzeusseu-Toukap A, Houssiau FA, Lauwerys BR - J. Cell. Mol. Med. (2011)

FLS and activated CD4 T cells produce two IL-7R α-chain isoforms. (A) IL-7R Western blots on protein extracts from FLS and PBMC, and IL-7R PCR on cDNA from duplicate TNF-α and IL-1β activated FLS (1), IL-2 and PHA activated CD4 T cells (2), antigen-activated CD8 T cell clones (3) and B-EBV cells (4). Arrows indicate the expected sizes of the membrane-bound IL-7R. (B) Sequencing of purified IL-7R PCR fragments indicates that FLS produce a full-length IL-7R α-chain and a truncated form of the IL-7R α-chain lacking exon 6 encoding the transmembrane domain, thereby resulting in a secreted form of the molecule.
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Related In: Results  -  Collection

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fig01: FLS and activated CD4 T cells produce two IL-7R α-chain isoforms. (A) IL-7R Western blots on protein extracts from FLS and PBMC, and IL-7R PCR on cDNA from duplicate TNF-α and IL-1β activated FLS (1), IL-2 and PHA activated CD4 T cells (2), antigen-activated CD8 T cell clones (3) and B-EBV cells (4). Arrows indicate the expected sizes of the membrane-bound IL-7R. (B) Sequencing of purified IL-7R PCR fragments indicates that FLS produce a full-length IL-7R α-chain and a truncated form of the IL-7R α-chain lacking exon 6 encoding the transmembrane domain, thereby resulting in a secreted form of the molecule.
Mentions: In our previous experiments, we demonstrated that RA patients have higher synovial IL-7R gene and protein expression as compared to osteoarthritis or lupus patients [12]. Moreover, we found that synovial overexpression of IL-7R in DMARD-resistant RA patients is associated with poor response to TNF blockade [6]. In these earlier experiments, anti IL-7R antibodies stained not only synovial mononuclear cells, but also synovial fibroblasts. Therefore, we wanted to further study the production and regulation of IL-7R by cultured FLS obtained from the joints of RA patients. Western blot and real-time qPCR experiments indicated that FLS express two isoforms of the molecule (Fig. 1A). Sequencing of the amplicons demonstrated that these isoforms correspond to the native IL-7R, and an alternatively spliced variant lacking exon 6 (transmembrane domain), which encodes a soluble form of the IL-7R (sIL-7R) (Fig. 1B).

Bottom Line: We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion.In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade.In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.

Show MeSH
Related in: MedlinePlus