Abstract
Levels of soluble tumour necrosis factor receptors (sTNFRs) are elevated in the circulation of patients with rheumatoid arthritis (RA). Although these receptors can act as natural inhibitors of tumour necrosis factor-α, levels of sTNFRs in RA appear to be insufficient to prevent tumour necrosis factor-α induced inflammation. The factors that regulate circulating levels of sTNFRs are unclear, but polymorphisms in the tumour necrosis factor receptor genes may play a role. We investigated the relationship between polymorphisms in the tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) genes and levels of sTNFRs in two groups of Caucasian RA patients: one with early (disease duration ≤2 years; n = 103) and one with established disease (disease duration ≥5 years; n = 151). PCR restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNF-RI gene and the T676G polymorphism in TNF-RII. Levels of sTNFRs were measured using ELISA. We also isolated T cells from peripheral blood of 58 patients with established RA with known TNF-R genotypes, and release of sTNFRs into the culture medium was measured in cells incubated with or without phytohaemagglutinin. Serum levels of the two sTNFRs (sTNF-RI and sTNF-RII) were positively correlated in both populations, and the level of each sTNFR was significantly higher in the patients with established disease (P < 0.0001). Multiple regression analyses corrected for age, sex and disease duration revealed a significant trend toward decreasing sTNF-RI and sTNF-RII levels across the TNF-RII genotypes (TT > TG > GG) of patients with established disease (P for trend = 0.01 and P for trend = 0.03, respectively). A similar nonsignificant trend was seen for early disease. No relationship with the TNF-RI A36G polymorphism was observed. sTNFRs released by isolated T cells exhibited a similar trend toward decreasing levels according to TNF-RII genotype, although only the association with levels of sTNF-RII was significant. Strong correlations were found between levels of circulating sTNFRs and levels released by T cells in vitro. Our data indicate that the T676G polymorphism in TNF-RII is associated with levels of sTNFRs released from peripheral blood T cells, and with circulating levels of sTNFR in patients with RA.
Highlights
Tumour necrosis factor (TNF)-α is a pleiotropic cytokine that is important in the pathogenesis of rheumatoid arthritis (RA), in which it plays a role in cartilage degradation, bone resorption, adhesion molecule expression, leucocyte infiltration, enzyme production and cytokine synthesis
In this study we report that polymorphism in the tumour necrosis factor receptor II (TNF-RII) gene, but not the tumour necrosis factor receptor I (TNF-RI) gene, is associated with circulating levels of TNF receptors in a population of Caucasian RA patients, and that this polymorphism is associated with levels of soluble TNF receptors (sTNFRs) released in vitro by isolated T cells from RA patients
Consistent with the findings reported by Cope and coworkers [16], levels of sTNF-RII were approximately three times greater on average than those of soluble tumour necrosis factor receptor I (sTNF-RI)
Summary
Tumour necrosis factor (TNF)-α is a pleiotropic cytokine that is important in the pathogenesis of rheumatoid arthritis (RA), in which it plays a role in cartilage degradation, bone resorption, adhesion molecule expression, leucocyte infiltration, enzyme production and cytokine synthesis (see reviews by Brennan and coworkers [1] and Choy and Panayi [2]). The actions of TNF-α are mediated through binding to two distinct cell surface receptors, namely tumour necrosis factor receptor I RI) and II (TNF-RII) [3,4] Both are transmembrane glycoproteins with a three domain structure: a multiple cysteine-rich motif bearing an extracellular domain that facilitates ligand binding; a hydrophobic membrane spanning domain; and an intracellular domain that mediates signal transduction.
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