Attenuation of experimental atherosclerosis by interleukin-19.
OBJECTIVE
Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms.


RESULTS
LDLR(-/-) mice fed an atherogenic diet and injected with either 1.0 or 10.0 ng/g per day recombinant mouse IL-19 had significantly less plaque area in the aortic arch compared with controls (P<0.0001). Weight gain, cholesterol, and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19-treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, interferon-γ, interleukin-1β, and interleukin-12β and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19-treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated that IL-19-treated mice have significantly less macrophage infiltrate compared with controls (P<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells, vascular smooth muscle cells, and bone marrow-derived macrophages with IL-19 resulted in a significant decrease in chemokine mRNA and mRNA stability protein human antigen R.


CONCLUSIONS
These data suggest that IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.
From the Department of Physiology, Independence Blue Cross Cardiovascular Research Center (S.E., K.G., S.E.K., R.N.E., R.S., J.M.R., M.V.A.) and Center for Inflammation, Translational and Clinical Lung Research (T.R., W.C.), Temple University School of Medicine, Philadelphia, PA; Department of Pathology, LSU Health Sciences Center, Shreveport, Shreveport, LA (W.O., J.G.T.); Department of Clinical Sciences, Lund University, Malmö, Sweden (L.M.B., M.F.G.); and Cardiology Department, Skåne University Hospital, Malmö, Sweden (I.G.).
Stephen
S
Ellison
Khatuna
K
Gabunia
Sheri E
SE
Kelemen
Ross N
RN
England
Rosario
R
Scalia
James M
JM
Richards
A Wayne
AW
Orr
Wayne
W
Orr
James G
JG
Traylor
Thomas
T
Rogers
William
W
Cornwell
Lisa M
LM
Berglund
Isabel
I
Goncalves
Maria F
MF
Gomez
Michael V
MV
Autieri
D000368:Aged; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology*; D007378:Interleukins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D015415:Biomarkers; C421250:IL19 protein, human; C498891:Il19 protein, mouse; D018836:Inflammation Mediators; D007378:Interleukins; D011973:Receptors, LDL; D011994:Recombinant Proteins; D014280:Triglycerides; D016753:Interleukin-10; D002784:Cholesterol
atherosclerosis; chemokines; interleukin-19; macrophages