| Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Many complicated factors interacted and interrelated biological processes contribute to atherogenesis. Atherosclerosis involves a large genetic network, not a simple linear pathway. This network extends to interactions with the many known risk factors for the disease and involves many cell types and organ systems.Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, as part of the inflammatory cascade, is considered to plays important roles in the atherogenesis. TNF-αproduced by several types of cell, such as macrophages, vascular endothelial cells (ECs) and smooth muscle cells (SMCs). TNF-αcould induce the production of cytokines, chemokines, and increase the expression of adhesion molecules on ECs and leukocytes, leading to the recruitment of monocytes / macrophages and infiltration into the subendothelial space of arteries, as well as subsequent activation of T-lymphocytes and the migration and proliferation of SMCs. However, its precise characters in primary stage of the disease remain unclear. To assess the influence of TNF-αon inflammatory factors in aorta and liver in apoE and TNF-αdouble mutant (AT) mice, a comparative study on early fatty-streak lesion, the mRNA level of target gene in aorta and liver of adolescent AT and apoE-null (apoE-/-) mice were achieved. The characteristics of expression of inflammatory factors, and early fatty-streak lesion relevance were analyzed. The plasma cytokines in 6-week-old AT and apoE-/- mice were also measured. The results showed that:Lipid accumulation in the intima of the aorta existed as early as 3 weeks of age in apoE-/- mice. Fatty-streak lesion was mild in AT mice but prominent in apoE-/- mice, at age of 6 weeks. Furthermore, most interesting findings indicate that mRNA levels of pro-atherosclerotic factors, i.e. IL-1β, IFN-γ, ICAM-1, VCAM-1, MCP-1, GM-CSF and NF-κB (p65) were significantly downregulated in AT mice. Whereas IL-2 and IκB-αwere upregulated in aorta of AT mice versus those in apoE-/- mice (p < 0.01) and the transcript levels of pro-inflammatory cytokines, such as IL-1β, IFN-γ, ICAM-1, VCAM-1, MCP-1 and GM-CSF, increased with atherogenesis progression. On the other hand, the expression of these inflammatory factors in the liver displayed somewhat similar fashion to those in the aorta. Moreover, the plasma lipids profile in AT mice showed less pro-atherogenic than that of apoE-/- mice. In conclusion, these results clearly indicated the TNF-αdeficiency retards early fatty-streak lesion in apoE-null background, due to altered expression levels of the chemokines, adhesion molecular and other inflammatory markers in aorta. Since the liver has a lower inflammatory state, our results raise the possibility that the lipid metabolism disorder just an initial factor and the formation and development of early fatty-streak lesion is more affected by local inflammation in the aorta at the early stage of the atherosclerosis. |
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