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(American Journal of Pathology. 2006;168:1396-1403.)
© 2006 American Society for Investigative Pathology

Interleukin-1ß and Signaling of Interleukin-1 in Vascular Wall and Circulating Cells Modulates the Extent of Neointima Formation in Mice

Janet Chamberlain*, David Evans*, Andrea King*, Rachael Dewberry*, Steven Dower{dagger}, David Crossman* and Sheila Francis*

From the Cardiovascular Research Unit* and Section of Functional Genomics,{dagger} University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, United Kingdom

Interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Here, we examined the role of IL-1 in arterial neointima formation. Carotid artery neointima was induced by ligation, and arteries were harvested 4 weeks after injury. The neointima/media of mice deficient in the IL-1 signaling receptor (IL-1R1–/–) was significantly reduced compared to IL-1R1+/+ controls (P < 0.01). IL-1R1+/+ mice receiving subcutaneous IL-1ra also had significantly reduced neointima/media compared with placebo (P < 0.05). IL-1ß–/– mice had reduced neointima/media compared to wild-type (P < 0.05), whereas IL-1{alpha}–/– mice were no different from controls. Mice deficient in the P2X7 receptor (involved in IL-1 release) or caspase-1 (involved in IL-1 activation) did not differ in their response to carotid ligation compared to controls. To examine the site of IL-1 signaling, we generated chimeric mice. IL-1R1+/+ mice receiving IL-1R1–/– marrow and IL-1R1–/– mice receiving IL-1R1+/+ marrow both had significantly reduced neointima/media compared with IL-1R1+/+ to IL-1R1+/+ (P < 0.05) but had significantly greater neointima/media than IL-1R1–/– to IL-1R1–/– controls (P < 0.05). These data confirm the importance of IL-1ß signaling in mediating arterial neointima formation and suggest the involvement of IL-1 signaling in both circulating and arterial wall cells. Furthermore, receptor antagonism may be a better therapeutic target than interruption of IL-1ß processing or release.




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