Interleukin-1beta and signaling of interleukin-1 in vascular wall and circulating cells modulates the extent of neointima formation in mice.
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-1beta(-/-) mice had reduced neointima/media compared to wild-type (P < 0.05), whereas IL-1alpha(-/-) mice were no different from controls. Mice deficient in the P2X(7) 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-1beta 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-1beta processing or release.
Cardiovascular Research Unit, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK. j.chamberlain@sheffield.ac.uk
Janet
J
Chamberlain
David
D
Evans
Andrea
A
King
Rachael
R
Dewberry
Steven
S
Dower
David
D
Crossman
Sheila
S
Francis
D000818:Animals; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology; D020170:Caspase 1 / Q000235:genetics; D002678:Chimera; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D007375:Interleukin-1; C546469:P2rx7 protein, mouse; D017472:Receptors, Interleukin-1; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D020170:Caspase 1