Interleukin-18 and macrophage migration inhibitory factor are associated with increased carotid intima-media thickening.
OBJECTIVE
Carotid intima-media thickening (IMT) is a form of vascular remodeling that has a strong genetic component. Recently, we discovered that in response to decreased carotid blood flow SJL mice developed the largest intima among 5 inbred strains. Because the SJL strain is prone to autoimmune diseases, we hypothesized that inflammation contributed to IMT in SJL mice.


RESULTS
We compared vascular remodeling (induced by 2 weeks of low flow) in 2 strains with small IMT (C3H/HeJ and C3HeB/FeJ) versus 2 strains with large IMT (FVB/NJ and SJL/J). Quantitative immunohistochemistry showed a dramatic increase in inflammatory cells per intima area in SJL compared with other strains. Microarray profiling of inflammatory gene mRNAs from carotids showed significant increases in interleukin (IL)-18 and Mif gene expression in SJL compared with C3HeB/FeJ mice. Increased expression of these genes was confirmed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Furthermore, greater cell proliferation in the intima of SJL accounted for increased intima-media thickening, whereas a higher level of apoptosis and a lower level of proliferation were observed in C3HeB/FeJ mice.


CONCLUSIONS
The present study indicates that increased expression of Mif and IL-18 cytokines is associated with intima-media thickening in SJL mice, likely by stimulating inflammation and proliferation.
Korshunov
Vyacheslav A
VA
Cardiovascular Research Institute, Department of Medicine, University of Rochester, NY 14642, USA.
Nikonenko
Tatiana A
TA
Tkachuk
Vsevolod A
VA
Brooks
Andrew
A
Berk
Bradford C
BC
D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000276:immunology* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000276:immunology* / Q000473:pathology; D002455:Cell Division; D005260:Female; D007150:Immunohistochemistry; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D013045:Species Specificity; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology; D017540:Tunica Media / Q000276:immunology / Q000473:pathology; D014657:Vasculitis / Q000276:immunology* / Q000473:pathology
D020382:Interleukin-18; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse