Differential role and tissue specificity of interleukin-1α gene expression in atherogenesis and lipid metabolism

Kamari, Yehuda; Werman-Venkert, Rachel; Shaish, Aviv; Werman, Ariel; Harari, Ayelet; Gonen, Ayelet; Voronov, Elena; Grosskopf, Itamar; Sharabi, Yehonatan; Grossman, Ehud; Iwakura, Yoichiro; Dinarello, Charles A.; Apte, Ron N.; Harats, Dror

doi:10.1016/j.atherosclerosis.2006.11.026

Cited by 100 publications

(78 citation statements)

References 36 publications

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“…However, Il1r1 -/-Apoe -/-mice exhibited significantly reduced plaque size across 4 locations at the aortic root ( Figure 1). These results are consistent with previous studies demonstrating a proatherogenic role for IL-1 signaling in aortic root atherosclerosis (20,22,23,25,29).…”

Section: Il-1r1 Deficiency Reduces Atherosclerotic Plaque Size At Thesupporting

confidence: 83%

“…IL-1α and IL-1β are found in human atherosclerotic plaques, where they are released primarily by endothelial cells and macrophages (18,19). Genetic inactivation and pharmacological inhibition of IL-1α, IL-1β, and IL-1R1 have been shown to decrease atherosclerotic plaque formation within the aortic root and thoracoabdominal aorta in mice (20)(21)(22)(23)(24)(25), demonstrating a pro-atherogenic role for IL-1 in promoting atherosclerotic lesion formation. However, these studies have focused almost exclusively on the effects of IL-1 on lesion size and the extent of lesion formation, and a comprehensive analysis of the role of IL-1 in regulating features of plaque stability and outward vessel remodeling in advanced atherosclerosis has not been performed.…”

Section: Introductionmentioning

confidence: 99%

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Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

Alexander¹,

Moehle²,

Johnson³

et al. 2012

J. Clin. Invest.

196

145

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Clinical complications of atherosclerosis arise primarily as a result of luminal obstruction due to atherosclerotic plaque growth, with inadequate outward vessel remodeling and plaque destabilization leading to rupture. IL-1 is a proinflammatory cytokine that promotes atherogenesis in animal models, but its role in plaque destabilization and outward vessel remodeling is unclear. The studies presented herein show that advanced atherosclerotic plaques in mice lacking both IL-1 receptor type I and apolipoprotein E (Il1r1 -/-Apoe -/-mice) unexpectedly exhibited multiple features of plaque instability as compared with those of Il1r1 +/+ Apoe -/-mice. These features included reduced plaque SMC content and coverage, reduced plaque collagen content, and increased intraplaque hemorrhage. In addition, the brachiocephalic arteries of Il1r1 -/-Apoe -/-mice exhibited no difference in plaque size, but reduced vessel area and lumen size relative to controls, demonstrating a reduction in outward vessel remodeling. Interestingly, expression of MMP3 was dramatically reduced within the plaque and vessel wall of Il1r1 -/-Apoe -/-mice, and Mmp3 -/-Apoe -/-mice showed defective outward vessel remodeling compared with controls. In addition, MMP3 was required for IL-1-induced SMC invasion of Matrigel in vitro. Taken together, these results show that IL-1 signaling plays a surprising dual protective role in advanced atherosclerosis by promoting outward vessel remodeling and enhancing features of plaque stability, at least in part through MMP3-dependent mechanisms.

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Section: Il-1r1 Deficiency Reduces Atherosclerotic Plaque Size At Thesupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

Alexander¹,

Moehle²,

Johnson³

et al. 2012

J. Clin. Invest.

196

145

View full text Add to dashboard Cite

show abstract

“…The involvement of IL-1a in CS-induced inflammatory responses is underappreciated, although IL-1a has been described to play an important role in inflammation (e.g. mice deficient in IL-1a are resistant to experimental colitis [22]). Also, in sterile inflammation, IL-1a, but not IL-1b, drives the neutrophilic inflammatory response to cell injury [23].…”

Section: Discussionmentioning

confidence: 99%

Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD

Pauwels

Bracke²,

Dupont³

et al. 2011

Eur Respir J

220

173

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Cigarette smoke (CS), the primary risk factor of chronic obstructive pulmonary disease (COPD), leads to pulmonary inflammation through interleukin-1 receptor (IL-1R)I signalling, as determined using COPD mouse models. It is unclear whether interleukin (IL)-1a or IL-1b, activated by the Nlrp3/caspase-1 axis, is the predominant ligand for IL-1RI in CS-induced responses.We exposed wild-type mice (treated with anti-IL-1a or anti-IL-1b antibodies), and IL-1RI knockout (KO), Nlrp3 KO and caspase-1 KO mice to CS for 3 days or 4 weeks and evaluated pulmonary inflammation. Additionally, we measured the levels of IL-1a and IL-1b mRNA (in total lung tissue by RT-PCR) and protein (in induced sputum by ELISA) of never-smokers, smokers without COPD and patients with COPD.In CS-exposed mice, pulmonary inflammation was dependent on IL-1RI and could be significantly attenuated by neutralising IL-1a or IL-1b. Interestingly, CS-induced inflammation occurred independently of IL-1b activation by the Nlrp3/caspase-1 axis. In human subjects, IL-1a and IL-1b were significantly increased in total lung tissue and induced sputum of patients with COPD, respectively, compared with never-smokers.These results suggest that not only IL-1b but also IL-1a should be considered as an important mediator in CS-induced inflammation and COPD.

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“…Disruption of the IL-1 and TNF-genes reduced early atherosclerosis development in apolipoprotein E (ApoE)-deficient mice without changing plasma lipid levels [26][27][28] . In addition, transplantation of IL-1 -and TNF--deficient bone marrow in irradiated ApoEdeficient mice reduced early plaque formation by 33% and 83%, respectively, compared to wild-type bone marrow-transplanted mice 27,29) . These findings suggest that blood cell-derived pro-inflammatory cytokines contribute to the progression of atherosclerosis.…”

Section: Gh Gm3mentioning

confidence: 99%

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

Matsumoto

Watanabe

Ueno

et al. 2010

JAT

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Aim:To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. Methods: Japanese White rabbits (n 8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 g/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 g/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. Results: Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p 0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. Conclusions: Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.J Atheroscler Thromb, 2010; 17:84-96.

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Differential role and tissue specificity of interleukin-1α gene expression in atherogenesis and lipid metabolism

Cited by 100 publications

References 36 publications

Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

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