A novel tylophorine analog NK-007 ameliorates colitis through inhibition of innate immune response

• Published in: International immunopharmacology 2012-12, Vol.14 (4), p.487-494
• Main Authors: Wen, Ti, Li, Yangguang, Wu, Meng, Chen, Xi, Han, Lin, Bao, Xiucong, Wang, Ziwen, Wang, Kailiang, Hu, Yanna, Zhou, Xinglong, Wu, Zhenzhou, Wang, Puyue, Hong, Zhangyong, Zhao, Liqing, Wang, Qingmin, Yin, Zhinan
• Format: Article
• Language: English
• Subjects: Acetic Acid - toxicity; Animal models; Animals; Anti-inflammatory activity; Biological and medical sciences; Bone marrow; Cell Line; Colitis; Colitis - chemically induced; Colitis - drug therapy; Dendritic cells; Dextran sulfate; Dextran Sulfate - toxicity; Immune response; Immunity, Innate - drug effects; Indolizines - therapeutic use; Inflammation; Interleukin 12; Lipopolysaccharides; Macrophages; Macrophages - drug effects; Male; Medical sciences; Mice; Molecular Structure; Monocytes; NF- Kappa B protein; NF-κB; Pharmacology. Drug treatments; Phenanthrenes - therapeutic use; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Rats; Rats, Wistar; Sodium; TNF-α; Tylophorine
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2012.08.008

In this study, we synthesized (±)-tylophorine malate (NK-007), an analog of tylophorine (DCB3503), and analyzed its anti-inflammatory effect in vivo using a dextran sulfate sodium (DSS)-induced colitis model and an acetic acid-induced colitis model. As indicated by disease activity index (DAI) and degree of macroscopic colonic damage, NK-007 can significantly suppress colitis. To delineate the underlying mechanism, we have explored the influence of NK-007 on the production of TNF-α by murine primary bone marrow-derived dendritic cells (BMDCs) as well as monocyte/macrophage cell line Raw 264.7 triggered by lipopolysaccharide (LPS). For both types of innate immune cells, NK-007 showed a potent TNF-α inhibitory effect, and has in addition reduced the expression of IL-12 in BMDCs. Moreover, Raw cells treated with NK-007 also showed decreased phosphorylation of NF-κB, which may explain the protective immune-regulatory effect of NK-007 for experimental colitis. ► NK-007 has treatment effects on DSS-induced and acetic acid-induced colitis. ► NK-007 inhibited TNF-α and IL-12 expression in BMDCs. ► NK-007 reduced TNF-α production in raw 264.7 cells. ► NK-007 ameliorated IBD through decreasing the phosphorylation of p65.