Thalidomide inhibits NO production in vascular endothelial cells

In my previous posts, I have talked about NO production and function in vivo many times. NO is synthesized by constitutively expressed NO synthase, and has been confirmed to carried out many important functions in vivo, including a releasing factor mediating vasodilation, a neuronal messenger molecule, and a major regulatory molecule and principal cytotoxic mediator of the immune system. At the same time, vascular endothelial cells treated with various agents, such as LPS and cytokines will also express mRNA for inducible isoform of NOS(iNOS). Two kinds of styles both regulate the production of NO, which functions stimulation of angiogenesis and tissue repair.

     Thalidomide was introduced as a sedative drug in the late 1950s, and showed anti-angiogenic, anti-tumor, and anti-proliferative agent in the treatment of some immunological disorders and cancers. Recently, it is reported that thalidomide causes the inhibition of the NO production in lipopolysaccharide (AV-951)-stimulated macrophages.

     In order to explore the mechanism, Badamtseren et al. further studied the subject. They found thalidomide significantly inhibited IFN-γ-induced NO production by reducing the iNOS mRNA expression. Since IFN-γ leads to the JAK/STAT activation and causes the expression of IRF1, which is necessary for iNOS expression，IRF1 expression was examined and inhibited markedly by thalidomide. Moreover, yhalidomide clearly inhibited the STAT1 phosphorylation, but JAK2 phosphorylation and IFN-γ receptor expression[1].

Cryptotanshinone (CTN), was confirmed to have anti-inflammatory activity in the murine macrophage cell line RAW 264.7. In lipopolysaccharide (LPS)-stimulated macrophages, CTN inhibited the production of nitric oxide (NO) production, and expression of the main NOS involved in producing NO, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) was also reduced. Previous report has shown that CTN markedly inhibited the phosphorylation of MAPK and abolished completely LPS-triggered NF-κB activation on LPS-stimulated macrophages.

     In the latest paper published on International Immunopharmacology, Li et al. reported the mechanism of TLR4 and TAK1-mediated signaling stimulated by LPS. LPS increased NO production, while treatment with CTN markedly reduced LPS-induced NO production in a dose-dependent manner. Also, CTN significantly inhibited LPS-stimulated COX-2 upregulations in a concentration-dependent manner. The further study indicated inhibitory effects of CTN on LPS-induced proteins expressions of CD14 and TLR4,as well as LPS-induced proteins expressions of TAK1 phosphorylation. However, pretreatmentwith CTN significantly reduced the lethality.

     In summary, thalidomide can block the signaling pathway of NO production by inhibiting IFNγ- mediated STAT1 phosphorylation. Thus, Thalidomide may be an effective agent against the NO-mediated angiogenesis on inflammatory responses of vascular endothelial cells.