Abstract
Objective: Human IL-18BP gene encodes at least four distinct isoforms (IL18BPa-d) derived by alternative splicing. Their presence in RA local inflammation is not yet examined. This study aimed to determine the messenger transcript and protein levels of IL-18BP isoforms in patients with Rheumatoid Arthritis (RA). Materials: The study comprises 65 rheumatic patients, 22 Osteoarthritis (OA), and 40 sex and age matched normal controls (NC). Peripheral blood mononuclear cells (PBMCs) and synovial fluids mononuclear cells (SFMCs) were prepared by using Ficoll-Hypaque procedure. The expression and presence of different isoforms were determined by using real-time PCR and ELISA respectively. Results: IL-18BP messenger transcript has been extremely expressed in synovial fluids (SF) and synovial tissues (ST) of RA patients compared to OA patients (p < 0.001). IL-18BP auto-antibodies were noticed in RA plasma and SF (41.7%; 37.9%), in OA-SF (9.0%), and in plasma of NC (4.0%). Comparable to different isoforms, isoform “c” showed significant local expression (p < 0.001) in RA-SFMC and systematic expression (p < 0.001) between RA- and NC-PBMCs, isoform “a” was least expressed. Isoform “c” and “d” proteins were solely detected by western blot in RA. Conclusions: This study emphasizes the local existence of isoform “c” and “d”, and the possible presence of autoantibodies against IL-18BPa in RA patients, which made a pea for further investigation, putting in place their actual role.
Highlights
Rheumatoid Arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the population in all parts of the world [1]
IL-18BP messenger transcript has been extremely expressed in synovial fluids (SF) and synovial tissues (ST) of RA patients compared to OA patients (p < 0.001)
The high expression of IL-18BP in RA synovium accompanied its high levels in RA serum [8], disease subsistence let us to postulate the presence of proteins or auto antibodies that may hinder the given proinflammatory effect of IL-18BP
Summary
Rheumatoid Arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the population in all parts of the world [1]. The inhibition of IL-18 was tested for the 4 purified isoforms by using different molar ratio of IL-18BP, complete inhibition of IL-18 activity on natural killer cells was observed at a twofold molar excess, while at equimolar ratios, the inhibition by IL18BPa was approximately 50%. The human isoforms IL-18BPa and IL-18BPc exhibited the greatest affinity for IL-18 with dissociation constants Kd of 399 pM and Kd of 2.94 nM, respectively and they inhibited 50% IL-18 at equimolar ratio, a notion explain unusual low molar ratio to observe inhibition of biological activity in a 24 hour bioassay, comparable to soluble receptors such as the IL-1 receptor type I and II and the TNF receptor p55 and p75, the molar excess required to inhibit 50% of biological activity of the respective ligands is at least five fold [5,6]. Quantitative comparision between isoforms is needed to validate the exact role of inactive isoform ‘d’
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