Abstract 48: Inhibition of Interleukin 27 Attenuates Atherosclerosis

Abstract

Interleukin (IL) 27 is an interesting cytokine as it has both pro- and anti-inflammatory properties. IL-27 binds to cytokine receptor WSX-1 to activate cells. In this experiment we determined the effect of IL-27 on atherosclerosis and blocked the function of IL-27 in vivo. This was achieved by injecting a lentivirus encoding the WSX-1 receptor lacking the intracellular domain with a human IgG2 tag (sWSX-1) in female LDL receptor deficient mice. The sWSX-1 protein was continuously released into the blood for at least 10 weeks and the responders (n=11) had a high serum hIgG level in comparison to the mice which received an empty virus (n=10), whereas the non-responders (n=9) did not show an increased hIgG level. After 10 weeks of atherogenic diet, mice were sacrificed . In vitro sWSX-1 was able to inhibit the IL-27-mediated IL-2 secretion in spleen cells. The in vivo blockade of IL-27 via the soluble receptor sWSX-1 resulted in a 31 % reduction in aortic lesion size in the responder group (2,7 x 10 5 μm 2 ± 2,2 x 10 4 ) compared to the control group (3,7 x 10 5 μm 2 ± 3,5 x 10 4 ). No change was measured in the non-responders (3,4 x 10 5 μm 2 ± 2,5 x 10 4 ) The lesion size negatively correlated with the concentration of the soluble receptor in the serum. sWSX-1 production did not affect the collagen content of the lesion, while there was a trend towards an increased macrophage content. FACS analysis showed that blockade of IL-27 increased the circulating T helper cell and cytotoxic T cell population by 2-fold. Surprisingly, no changes were detected in the Th1 and Th17 populations. There was a 5-fold increase in the percentage circulating regulatory T cells in the presence of sWSX-1. Furthermore, CCR2 expression on circulating Ly6C low monocytes was reduced by 44 %. The proliferation of spleen cells showed no change between the control and mice with overexpression of sWSX-1. Taken together these results indicate that blockade of interleukin 27 reduces lesion formation by inducing a less inflammatory immune status.