Abstract
IκBNS is a nuclear IκB protein which negatively regulates nuclear factor-κB activity. We demonstrated that IκBNS deficiency accelerates atherosclerosis in LDL receptor-deficient (LDLr−/−) mice via increased interleukin (IL)-6 production by macrophages. Previous studies showed that the increase in IL-6 might contribute to the development of atherosclerotic lesions. However, whether an anti-mouse IL-6 receptor antibody (MR16-1) can protect atherosclerotic lesions in atherogenic mice remains to be elucidated. We investigated atherosclerotic lesions in LDLr−/− and IκBNS−/−/LDLr−/− mice after 16 weeks consumption of a high-fat diet. All mice received intraperitoneal injections of MR16-1 or phosphate-buffered saline (PBS) (control) once a week during a high-fat diet consumption. Treatment of MR16-1 yielded no adverse systemic effects, and we detected no significant differences in serum cholesterol levels in either group. The atherosclerotic lesions were significantly increased in IκBNS−/−/LDLr−/− compared with LDLr−/− mice (p < 0.01) under treatment of PBS. However, MR16-1 treatment abolished the significant difference of atherosclerotic lesions between IκBNS−/−/LDLr−/− and LDLr−/− mice. Interestingly, MR16-1 also significantly decreased atherosclerotic lesions in LDLr−/− mice compared with PBS treatment (p < 0.05). Immunostaining revealed percent phospho-STAT3-positive cell were significantly decreased in the atherosclerotic lesions of MR16-1 treated both IκBNS−/−/LDLr−/− and LDLr−/− mice compared with PBS-treated mice, indicating MR16-1 could suppress atherosclerotic lesions via the inhibition of IL-6–STAT3 signaling pathway. This study highlights the potential therapeutic benefit of anti-IL-6 therapy in preventing atherogenesis induced by dyslipidemia and/or inflammation.
Highlights
Nuclear factor-κB (NF-κB) plays essential roles in mediating immune systems
MR16-1 treatment significantly reduced atherosclerotic lesions in both LDLr−/− and IκBNS−/−/LDLr−/− mice compared with phosphate-buffered saline (PBS) treatment (Figure 4). These results show that an anti-mouse IL-6 receptor antibody significantly suppresses IκBNS in both LDLr−/− and IκBNS−/−/LDLr−/− mice without major confounding effects on low-density lipoprotein (LDL)-cholesterol or high-density lipoprotein (HDL)-cholesterol, suggesting that inhibition of IL-6 might be significantly effective to prevent atherogenesis
IL-6 stimulates growth of promoters of macrophage and vascular smooth muscle cells, which are major components of plaque [11,12,13], and IL-6 expression is detected in human atherosclerotic lesions [14]
Summary
Nuclear factor-κB (NF-κB) plays essential roles in mediating immune systems. After translocation of NF-κB from the cytoplasm to the nucleus, nuclear proteins that are structurally similar to cytoplasmic IκBs take part in the mediating of NF-κB transcriptional activity, as activators or inhibitors, by associating with NF-κB subunits [2]. Anti-IL-6 Therapy for Atherosclerosis proteins, the role of IκBNS in the development of atherosclerosis is poorly understood. Our previous study demonstrated that deficiency of IκBNS induces atherogenesis in LDL receptor-deficient (LDLr−/−) mice fed a high-fat diet and increases in interleukin (IL)-6 production by macrophages, indicating that IκBNS plays an important role in the suppression of atherosclerotic lesions in vivo [3]. Whether or not increased IL-6 production in IκBNS-deficient LDLr−/− mice accelerates atherogenesis remains undetermined
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