BACKGROUND: Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis. METHODS AND RESULTS: To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE(+/-)-IL-6(+/-) and ApoE(+/-)-IL-6(-/-) mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50 microl live Porphyromonas gingivalis (P.g.) (10(7)CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE(+/-)-IL-6(-/-) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-IL-6(+/-) mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE(+/-)-IL-6(-/-) mice were significantly higher than ApoE(+/-)-IL-6(+/-) mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE(+/-)-IL-6(-/-) mice compared to ApoE(+/-)-IL-6(+/-) mice, irrespective of diet or inoculation. CONCLUSION: The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.
BACKGROUND: Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis. METHODS AND RESULTS: To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE(+/-)-IL-6(+/-) and ApoE(+/-)-IL-6(-/-) mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50 microl live Porphyromonas gingivalis (P.g.) (10(7)CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE(+/-)-IL-6(-/-) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-IL-6(+/-) mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE(+/-)-IL-6(-/-) mice were significantly higher than ApoE(+/-)-IL-6(+/-) mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE(+/-)-IL-6(-/-) mice compared to ApoE(+/-)-IL-6(+/-) mice, irrespective of diet or inoculation. CONCLUSION: The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.
Authors: A S Plump; J D Smith; T Hayek; K Aalto-Setälä; A Walsh; J G Verstuyft; E M Rubin; J L Breslow Journal: Cell Date: 1992-10-16 Impact factor: 41.582
Authors: Ben van Ommen; Jaap Keijer; Robert Kleemann; Ruan Elliott; Christian A Drevon; Harry McArdle; Mike Gibney; Michael Müller Journal: Genes Nutr Date: 2008-06-25 Impact factor: 5.523
Authors: Claudia Mickael; Rahul Kumar; Daniel Hernandez-Saavedra; Biruk Kassa; Linda Sanders; Dan Koyanagi; Sue Gu; Michael H Lee; Rubin M Tuder; Brian B Graham Journal: Am J Respir Cell Mol Biol Date: 2019-07 Impact factor: 6.914
Authors: Yu-Hsiung Wang; Jin Jiang; Qiang Zhu; Amer Z AlAnezi; Robert B Clark; Xi Jiang; David W Rowe; Frank C Nichols Journal: Infect Immun Date: 2010-06-28 Impact factor: 3.441
Authors: R Angelo de Claro; Xiaodong Zhu; Jingjing Tang; Vicki Morgan-Stevenson; Barbara R Schwartz; Akiko Iwata; W Conrad Liles; Elaine W Raines; John M Harlan Journal: Am J Pathol Date: 2011-05-06 Impact factor: 4.307
Authors: Isola A M Brown; Lukas Diederich; Miranda E Good; Leon J DeLalio; Sara A Murphy; Miriam M Cortese-Krott; Jennifer L Hall; Thu H Le; Brant E Isakson Journal: Arterioscler Thromb Vasc Biol Date: 2018-09 Impact factor: 8.311
Authors: Nicole E Hastings; Ryan E Feaver; Monica Y Lee; Brian R Wamhoff; Brett R Blackman Journal: Arterioscler Thromb Vasc Biol Date: 2009-02-19 Impact factor: 8.311