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Inhibiting IL-6 trans-signalling with soluble gp130Fc potently reduces the incidence and severity of collagen-induced experimental arthritis [Abstract]

Smale, Shaun, Carty, Sara Madelaine, Goodfellow, Rhian Mair, Choy, Ernest Ho-Sing, Rose-John, Stefan, Jones, Simon Arnett and Williams, Anwen SIan 2011. Inhibiting IL-6 trans-signalling with soluble gp130Fc potently reduces the incidence and severity of collagen-induced experimental arthritis [Abstract]. Arthritis and Rheumatism 63 (s10) , S446-S447.

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Abstract

Background/Purpose: Cytohistomorphological analysis of the synovial joint provides researchers with an opportunity to unmask specific intra- and extra- cellular mechanisms that regulate the switch from acute to chronic pathology in arthritis. The signal transducer and activator of transcription (STAT) pathway orchestrates this transition and steers the effector functions of interleukin-6 (IL-6) within the inflamed joint. We used a pertinent inflammatory arthritis model, murine collagen-induced arthritis (mCIA), to define the timecourse of STAT3 expression within the inflamed joint and to test the potency of timely targeted therapy with an inhibitor of IL-6 trans-signalling (sgp130Fc). Method: Joint tissues were collected (pre and post arthritis) over the timecourse of mCIA. IL-6, soluble IL-6 receptor (sIL-6R) and STAT3 were measured in joint tissue homogenates by ELISA. To test sgp130Fc’s efficacy, 2.5mg/Kg was injected daily. Control mice received either etanercept (2.5mg/Kg daily) or vehicle; they were administered using an identical dosing regimen. Arthritis severity was gauged macroscopically in each paw; the sum of scores provided a clinical arthritis index (CAI) for each mouse. Therapeutic outcome was determined microscopically in serial histological sections taken from joint tissue specimens at end point. Result: In early mCIA, joint tissue homogenates recorded significant increases in IL-6 (P<0.01), sIL-6R (P<0.05) and STAT3 (P<0.05) levels; they coincided with arthritis onset. sgp130Fc treatment was therefore initiated at arthritis onset. sgp130Fc and etanercept delayed mCIA onset, after 5 doses arthritis incidence was 0% (sgp130Fc) versus 17% (etanercept) and 83% (vehicle). At endpoint (day 7 therapy) all mice had arthritis; CAI (P<0.05) and paw diameters (P<0.05) were significantly reduced in sgp130Fc and etanercept compared with vehicle controls. Histological damage was less severe in the etanercept group versus vehicle controls, but not statistically significantly different. All histological parameters were significantly lower in sgp130Fc vs vehicle controls (synovial hyperplasia (P<0.01), synovial tissue infiltrate (P<0.01)). Cytomorphometric analysis revealed that synovial Ly-6G+-neutrophils (P<0.05), F4/80+-macrophages (P<0.01) and CD3+-T-cells (P<0.01) counts were also significantly lower in sgp130Fc vs. vehicle controls. Tissue protective functionality of sgp130Fc was highlighted further by the absence of lymphoid aggregates, diminutive tartrate resistant acid phosphatase staining for osteoclasts and significantly less bone erosions (P<0.05) compared with vehicle controls. At the dosing regimen under investigation, electrophoretic mobility shift assays revealed that sgp130Fc lowered the level of nuclear factor-kappa B (NFkB) and STAT activation (predominantly STAT3) in joint tissues at endpoint whilst etanercept caused a partial reduction in NFkB. Conclusion: Timely targeted inhibition of IL-6 trans-signalling with sgp130Fc potently reduces clinical disease severity in an experimental model of arthritis. Selective blockade of IL-6 trans-signalling could have therapeutic applicability in the management of rheumatoid arthritis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: inflammatory arthritis
Additional Information: Abstracts of the American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting Chicago, Illinois November 4-9, 2011.
Publisher: Wiley-Blackwell
ISSN: 0004-3591
Last Modified: 12 Jul 2019 20:17
URI: http://orca.cf.ac.uk/id/eprint/43503

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