Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Mechanisms Underlying the Generation of Soluble IL-6 Soluble Receptor (sIL-6R) in Rheumatoid Arthritis: mRNA Alternative Splicing and Proteolytic Cleavage As Independent Contributors.

Lamas1,  Jose Ramon, Rodriguez-Rodriguez2,  Luis, Tornero-Esteban2,  Pilar, Abasolo2,  Lydia, Varade1,  Jezabel, Alvarez-Lafuente1,  Roberto, Villafuertes2,  Esther

Hospital clinico San Carlos, Madrid, Spain
Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain

Background/Purpose:

Given that IL-6 bioactivity is greatly modulated through trans-signalling by sIL-6R/IL-6 complexes, the aim of this study was to describe the contribution of proteolytic cleavage and alternative splicing mechanisms in the generation of soluble forms of IL-6 receptor (sIL-6R) and their pathological relevance in rheumatoid arthritis (RA).

Methods:

RA patients were randomly selected from a cohort of subjects previously genotyped for the non-synonymous polymorphism rs8192284 (A>C) of the IL-6R gene resulting in an amino acid change located at the proteolytic cleavage site (D358A). Expression of the membrane-bound IL-6 receptors (IL-6R and gp130) was evaluated in different peripheral blood populations by flow cytometry. Plasma concentrations of sIL-6R, soluble gp130, the sIL-6R/IL-6 complexes and the proteolytic enzyme responsible for the cleavage (TACE/ADAMTS17) were measured by ELISA. The contribution of alternative splicing in the generation of sIL-6R was assessed by qRT-PCR.

Results:

No differences were found in IL-6R membrane expression according to the rs8192284 variation. sIL-6R plasma levels were positively associated with the presence of the C allele, AA: 79.36±5.8 ng/ml, AC: 100.50±4.05 ng/ml, CC: 128.9±6.8 ng/ml, p < 0.0001. Only 32% of the IL-6 present in plasma was not bound to sIL-6R. The contributions of alternative splicing and TACE concentrations were independent of the genotype studied.

Conclusion:

Both mechanisms of sIL-6R generation coexist in RA. The rs8192284 polymorphism determines differences in sIL-6R plasma levels through differential proteolytic cleavage efficiency mediated by TACE. In addition, most IL-6 molecules form IL-6/sIL-6R complexes, suggesting the important contribution of trans-signalling in modulating the biological effects of IL-6 in RA.

To cite this abstract, please use the following information:
Lamas, Jose Ramon, Rodriguez-Rodriguez, Luis, Tornero-Esteban, Pilar, Abasolo, Lydia, Varade, Jezabel, Alvarez-Lafuente, Roberto, et al; Mechanisms Underlying the Generation of Soluble IL-6 Soluble Receptor (sIL-6R) in Rheumatoid Arthritis: mRNA Alternative Splicing and Proteolytic Cleavage As Independent Contributors. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :383
DOI:

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