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FRI0045 Therapeutic Blockade of Interleukin-6 Trans-Signalling Restores Vascular Function in Murine Collagen Induced Arthritis
  1. R. Davies1,
  2. J. Williams1,
  3. K. Sime1,
  4. E. Hughes2,
  5. L. Jordan1,
  6. C. Rawlings1,
  7. D. Lang3,
  8. S. Jones1,
  9. S. Rose-John4,
  10. A. Williams1,
  11. E. Choy1
  1. 1CREATE Centre, Division of Infection and Immunity, Cardiff University
  2. 2Immunology & Cancer Immunotherapy, Infection and Immunity
  3. 3Institute of Molecular and Experimental Medicine, Cardiff University, Cardiff, United Kingdom
  4. 4Institüt of Biochemistry, Christian-Albrecht Universität, Kiel, Germany

Abstract

Background Mortality is increased in rheumatoid arthritis (RA), mainly due to cardiovascular disease (CVD). While molecular mechanisms underlining this observation are unknown, systemic elevations in inflammatory cytokines, eg interleukin (IL)-6 frequently correlate with increased cardiovascular risk. IL-6 plays roles in both immune homeostasis and driving chronic disease progression. Control of these processes is regulated by two modes of IL-6 signalling; classical IL-6 signalling and IL-6 trans-signalling. Cellular responses controlled by IL-6 trans-signalling are mediated via soluble IL-6 receptor (sIL-6R) and is widely considered to promote pro-inflammatory outcomes. Importantly, a genetic polymorphism within IL6R enhances circulating sIL-6R level and is associated with CVD incidence in the general population. Biological drugs against IL-6 or IL-6R block both classical and trans-signalling. However it is advocated that selective inhibition of IL-6 trans-signalling may reduce clinical complications associated with a more global intervention strategy. Murine collagen induced arthritis (mCIA) is associated with vascular dysfunction, with reduced aortic constriction to 5-HT. Here, we found systemic alterations in vascular tone, as a response to mCIA, was attributable to IL-6 trans-signalling.

Objectives Investigations assessed whether inhibition of IL-6 trans-signalling using the selective antagonist sgp130Fc affected aortic constriction as an index of vascular dysfunction in mCIA.

Methods Arthritis was induced in 8 week old male DBA/1 mice by type-II collagen, as previously described1. Animals were administered IV sgp130Fc (2.5mg/kg) or PBS weekly from day 21. Arthritis severity was monitored daily from day 21–30. Vasoconstriction of aortic rings in response to 5-HT was monitored as an index of vascular function using isometric tension myography. Results are expressed as mean ± SEM (n=10).

Results When compared with PBS controls (Arthritis Index:4.3±1.1), disease severity was significantly (P<0.05) reduced in sgp130Fc (1.5±0.6) treated mice (Fig1A). PBS control mice with mCIA had reduced vasoconstriction (developed tension 8.5±0.6mN for non-immunised mice, 5.8±0.8mN for mCIA mice; P<0.05). Significantly, improvement of disease activity observed for sgp130Fc treated animals was associated with normalisation of vascular function (developed tension 8.1±0.6mN).

Conclusions Consistent with previous reports1, sgp130Fc reduced arthritis in mCIA. Sgp130Fc also restored vascular function. Selective IL-6 trans-signaling blockade by sgp130Fc is a promising therapeutic strategy for both RA and its associated CVD. Further work is needed to elucidate the role of IL-6 trans-signaling in pathogenesis of vascular dysfunction in mCIA and RA.

  1. Nowell MA, Williams AS, Carty SA, Scheller J, Hayes AJ, Jones GW, Richards PJ, Slinn S, Ernst M,Jenkins BJ, Topley N, Rose-John S, Jones SA. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol. 2009 Jan 1;182(1):613–22.

Acknowledgement Dr Ruth Davies is supported by an Arthritis Research UK Clinical Fellowship. CREATE Centre is funded by Arthritis Research UK & Health and Care Research Wales.

Disclosure of Interest None declared

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