Immunomodulatory activity of betulinic acid by producing pro-inflammatory cytokines and activation of macrophages.
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.
Yun
Yunha
Y
Department of Pharmacy, Sahmyook University, 26-21 Gongreung-2 Dong, Seoul 139-742, Korea.
Han
Shinha
S
Park
Eunjung
E
Yim
Dongsool
D
Lee
Sookyeon
S
Lee
Chong-Kil
CK
Cho
Kyunghae
K
Kim
Kyungjae
K
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018836:Inflammation Mediators / Q000378:metabolism*; D031333:Lycopus; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D053978:Pentacyclic Triterpenes; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018515:Plant Leaves; D018547:Plant Stems; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000094062:Betulinic Acid
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D014315:Triterpenes; D000094062:Betulinic Acid