Immunomodulatory activity of betulinic acid by producing pro-inflammatory cytokines and activation of macrophages

• Published in: Archives of pharmacal research 2003-12, Vol.26 (12), p.1087-1095
• Main Authors: Yun, Yunha, Han, Shinha, Park, Eunjung, Yim, Dongsool, Lee, Sookyeon, Lee, Chong-Kil, Cho, Kyunghae, Kim, Kyungjae
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - isolation & purification; Adjuvants, Immunologic - pharmacology; Animals; Cell Line; Cells, Cultured; Cytokines - biosynthesis; Cytokines - physiology; Dose-Response Relationship, Drug; Inflammation Mediators - metabolism; Lycopus; Macrophage Activation - drug effects; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Male; Mice; Plant Components, Aerial; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plant Leaves; Plant Stems; Triterpenes - chemistry; Triterpenes - isolation & purification; Triterpenes - pharmacology
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/bf02994763

Betulinic acid (BA), a pentacyclic triterpene isolated from Lycopus lucidus, has been reported to be a selective inducer of apoptosis in various human cancer and shown anti-inflammatory and immunomodulatory properties. We postulated that BA modulates the immunomodulatory properties at least two groups of protein mediators of inflammation, interleukin-1beta (IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) on the basis of the critical role of the monocytes and tissue macrophages in inflammatory and immune responses. TNF-alpha and IL-1beta were produced by BA in a dose dependent manner at concentration of 0.625 and 10 microg/mL. The production of NO associated with iNOS was inhibited when treated with LPS at the concentration of 2.5 to 20 microg/mL of BA whereas COX-2 expression was decreased at 2.5 to 20 microg/mL. These modulations of inflammatory mediators were examined in LPS-stimulated RAW 264.7 cells and peritoneal macrophages. The morphology of macrophage was also examined and enhanced surface CD 40 molecule was expressed when treated BA at 0.625 to approximately 5 microg/mL with or without LPS. Furthermore, BA (20 microg/mL) enhanced apoptosis by producing DNA ladder in the RAW 264.7 cells. Our results indicated that BA induced activation of macrophage and pro-inflammatory cytokines. This may provide a molecular basis for the ability of BA to mediate macrophage, suppress inflammation, and modulate the immune response.