There was a highly significant distortion between patients with RA and controls in the distribution of beta2AR polymorphisms at codon 16, contributing (together with the HLA-DR alleles) to the genetic background of RA.
Objective
Dysregulated apoptosis of monocytes is a pathogenic feature of rheumatoid arthritis (RA). The aim of this study was to investigate the role of TRAIL and TRAIL‐induced apoptosis in patients with RA.
Methods
Cell surface expression and serum concentrations of TRAIL were determined in 63 patients with RA, and TRAIL‐induced monocyte apoptosis was quantified. Surface expression of TRAILR‐1, TRAILR‐2, TRAILR‐3, TRAILR‐4, CXCR1, and CXCR2 was determined, and intracellular signal transduction was investigated. In 8 patients with RA, clinical and laboratory parameters of disease activity were investigated longitudinally, before and after initiation of treatment with tumor necrosis factor (TNF) inhibitors.
Results
Serum concentrations of both TRAIL and interleukin‐8 (IL‐8) were increased in patients with RA, while cell surface expression of the TRAIL receptors TRAILR‐1, TRAILR‐2, TRAILR‐3, and TRAILR‐4 was diminished. TRAIL‐induced monocyte apoptosis was significantly decreased in RA due to increased TRAIL‐induced IL‐8 secretion by RA monocytes. The combined effect of TRAIL and IL‐8 on monocytes resulted in activation of antiapoptotic pathways, including p42/44 MAPK and p38. Susceptibility to TRAIL‐induced apoptosis was restored in RA monocytes after 3 months of TNF inhibition.
Conclusion
In RA, circulating monocytes with the potential to produce proinflammatory cytokines appear to have defects in several pathways of apoptosis induction, among which is a deficiency in TRAIL‐induced apoptosis. Although this resistance to apoptosis might contribute to perpetuation of the disease, it remains to be determined whether specific induction of apoptosis could be therapeutically beneficial.
Recently, studies in adult rheumatoid arthritis patients have shown an association with four single-nucleotide polymorphisms (SNPs) in the 3.7-kb regulatory region of human corticotropin-releasing hormone (hCRH) gene located at positions -3531, -3371, -2353, and -684 bp. Three of these novel polymorphisms are in absolute linkage disequilibrium, resulting in three combined alleles, named A1B1, A2B1, and A2B2. To study whether the described polymorphic nucleotide sequences in the 5' region of the hCRH gene interfere with binding of nuclear proteins, an electric mobility shift assay (EMSA) was performed. At position -2353 bp, a specific DNA protein complex was detected for the wild-type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). In contrast, no difference could be detected for the other SNPs. However, at position -684, a quantitative difference in protein binding due to cAMP incubation could be observed. To further investigate whether these SNPs in the CRH promoter are associated with an altered regulation of the CRH gene, we performed a luciferase reporter gene assay with transiently transfected rat pheochromocytoma cells PC12. Incubation with 8-Br-cAMP alone or in combination with cytokines enhanced significantly the promoter activity in PC12 cells. The promoter haplotypes studied exhibited a differential capacity to modulate CRH gene expression. In all our experiments, haplotype A1B1 showed the most pronounced influence on promoter activity. Taken together, our results demonstrate a differential binding capacity of nuclear proteins of the promoter polymorphisms resulting in a different gene regulation. Most probably the SNP at position -2,353 plays a major role in mediating these differences.
Rheumatoid arthritis (RA) is a chronic rheumatic disease of unknown aetiology and variable severity. It is now well known that several risk factors are involved in its pathogenesis, including genetic factors and sex hormones as well as environmental factors, i.e. infections and stress. In particular stress is now recognised as an important risk factor for the onset and even more for the modulation of disease activity in RA. Many studies have clearly shown that chronic mild stress (family or professional stress) may lead to proinflammatory effects, increasing disease activity. Furthermore, a positive correlation between the stress level at the onset of RA and radiological progression could be demonstrated. The onset of RA was associated with moderate stress at work, underlining the possible interactions between the various stress systems and the immune system. In this respect it could be demonstrated that coping strategies reduce stress episodes and change stress management with a positive impact on disease activity in RA. However, more studies are warranted to further explore the pathophysiological implications of stress on onset and activity of chronic autoimmune diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.