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. Methods and 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. Conclusion - 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.