TY - JOUR
T1 - Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α
AU - Kamari, Yehuda
AU - Shaish, Aviv
AU - Shemesh, Shay
AU - Vax, Einav
AU - Grosskopf, Itamar
AU - Dotan, Shahar
AU - White, Malka
AU - Voronov, Elena
AU - Dinarello, Charles A.
AU - Apte, Ron N.
AU - Harats, Dror
N1 - Funding Information:
Y. Kamari is supported by the Talpiot Medical Leadership Program Award, Sheba Medical Center, Tel Hashomer, Israel, the Sami and Angela Shamoon Vascular Biology Research Fund, and the Israel Ministry of Health Chief Scientist’s Office #3953. CA. Dinarello is supported by NIH Grant AI-15614. We thank Dr. Esfir Ulman, Hanna Levkowitz, Boris Feldman and Zehava Shabtay for technical assistance.
PY - 2011/2/11
Y1 - 2011/2/11
N2 - Objective: Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. Methods: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/- Results: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. Conclusion: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.
AB - Objective: Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. Methods: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/- Results: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. Conclusion: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.
KW - ApoE-deficient mice
KW - Atherosclerosis
KW - Cytokines
KW - IL-1
KW - Macrophages
UR - http://www.scopus.com/inward/record.url?scp=79651474891&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2011.01.008
DO - 10.1016/j.bbrc.2011.01.008
M3 - Article
AN - SCOPUS:79651474891
SN - 0006-291X
VL - 405
SP - 197
EP - 203
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
