Differential role and tissue specificity of interleukin-1alpha gene expression in atherogenesis and lipid metabolism.
OBJECTIVE
We examined the role of IL-1alpha and IL-1beta expressed by bone marrow-derived cells in atherogenesis and lipid metabolism.


RESULTS
We first studied the effect of atherogenic diet on wild-type C57BL/6 IL-1alpha or IL-1beta deficient mice. IL-1alpha KO resulted in a comparatively higher total cholesterol levels, compared to WT and IL-1beta KO mice (398+/-10; 266+/-19; 223+/-13 mg/dl, respectively, p<0.001), due to higher non-HDL cholesterol. Nevertheless, aortic sinus lesion area was 56% lower in IL-1alpha KO (p<0.05) and 50% lower in IL-1beta KO (p=0.08), compared to WT mice. Likewise, SAA levels in IL-1alpha KO mice were markedly lower compared to WT and IL-1beta KO mice (31+/-14; 220+/-33 and 106+/-39 microg/ml, respectively, p<0.001). To study the specific role of bone marrow-derived IL-1, irradiated C57BL/6 mice were transplanted with either IL-1+/+, IL-1alpha-/- or IL-1beta-/- bone marrow cells. Despite similar lipoprotein levels, aortic sinus lesion area was 59% lower in IL-1alpha-/- transplanted (p<0.05) compared to IL-1+/+ transplanted mice. Lesion area in IL-1beta-/- was 33% lower than in IL-1+/+ recipient mice, but it was not statistically significant.


CONCLUSIONS
We demonstrated that early lesion formation is accelerated specifically by bone marrow-derived IL-1alpha. Furthermore, we showed that the expression of IL-1alpha in cells other than the bone marrow plays a significant role in non-HDL cholesterol metabolism.
Kamari
Yehuda
Y
Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel.
Werman-Venkert
Rachel
R
Shaish
Aviv
A
Werman
Ariel
A
Harari
Ayelet
A
Gonen
Ayelet
A
Voronov
Elena
E
Grosskopf
Itamar
I
Sharabi
Yehonatan
Y
Grossman
Ehud
E
Iwakura
Yoichiro
Y
Dinarello
Charles A
CA
Apte
Ron N
RN
Harats
Dror
D
D000682:Amyloid / Q000097:blood / Q000737:chemistry; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D016026:Bone Marrow Transplantation; D008076:Cholesterol, HDL / Q000378:metabolism; D005786:Gene Expression Regulation; D053582:Interleukin-1alpha / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000682:Amyloid; D008076:Cholesterol, HDL; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008055:Lipids; D008074:Lipoproteins