Background/Purpose:

Mortality is increased in rheumatoid arthritis (RA), mainly due to cardiovascular disease (CVD). While molecular mechanisms underlining this clinical observation are unknown, systemic elevations in inflammatory cytokines such as interleukin (IL)-6 frequently correlate with increased cardiovascular risk. Importantly, IL-6 plays important 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 receptor 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 deleterious pro-inflammatory outcomes. Importantly, a genetic polymorphism within IL6R enhances circulating sIL-6R levels and is associated with CVD incidence in the normal population. Biological drugs against IL-6 (e.g. olokizumab) or IL-6R (e.g. tocilizumab) block both classical and trans-signalling. However it is advocated that selective inhibition of IL-6 trans-signalling may reduce the incidence of clinical complications associated with a more global intervention strategy. Previously, murine collagen induced arthritis (mCIA) has been associated with vascular dysfunction, with reduced aortic constriction to 5-hydroxytryptamine (5-HT)[1]. Here, we found systemic alterations in vascular tone, as a response to mCIA, was attributable to the action of IL-6 trans-signalling.

Methods:

Arthritis was induced in 8 week old male DBA/1 mice by type-II collagen, as previously described[2]. Animals were intravenously administered sgp130Fc (2.5mg/kg) or PBS weekly from day 21 after immunisation with type-II collagen. Arthritis severity was monitored daily from day 21 to 30. Vasoconstriction of isolated 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:

Figure 1 (A) Significant difference in Arthritis Index over time in mice administered spg130Fc compared with PBS. (B) Vasoconstriction concentration-response curves to 5-HT in aortic rings. N=10

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 (Figure1A). The induction of arthritis in PBS control animals was accompanied by reduced vasoconstriction (developed tension 8.5±0.6 mN for non-immunised mice, compared with 5.8±0.8 mN for mice with CIA; P<0.05). Significantly, improvement of disease activity observed for sgp130Fc treated animals was associated with normalisation of vascular function (developed tension 8.1±0.6 mN).

Conclusion:

Consistent with previous reports², 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-signalling in the pathogenesis of vascular dysfunction in both mCIA and RA.