Andrographolide Inhibits IFN-γ and IL-2 Cytokine Production and Protects Against Cell Apoptosis

Abstract

Andrographolide is the main labdane diterpene present in Andrographis paniculata. Two lines of evidence report immunostimulant and anti-inflammatory properties for andrographolide in different models. Using murine T-cells in vitro we demonstrated that andrographolide and to a lesser extent, 14-deoxyandrographolide (14-DAP), reduced significantly, in a dose-dependent manner, the IFN-gamma production induced by concanavaline A (CON-A), with an IC50 of 1.7 +/- 0.07 microM and 35.8 +/- 0.50 microM, respectively. Andrographolide, but not 14-DAP, inhibited partially the IL-2 production induced by CON-A. Andrographolide at doses of 5 and 10 microM reduced the extracellular-signal-regulated protein kinase (ERK1/2) phosphorylation induced by CON-A, whereas 14-DAP only reduced ERK1 and partially the ERK2 phosphorylation. The inhibition of ERK1/2 phosphorylation was associated to a decrease in the IFN-gamma production, due that UO126, a specific ERK1/2 inhibitor, also reduced the IFN-gamma production in murine T-cells induced by CON-A. Additionally, andrographolide and to a lesser extent 14-DAP, at doses of 50 microM and 100 microM, respectively, reduced the apoptosis induced by hydrocortisone and PMA in thymocytes, which was associated to a decrease in caspase-3 like activity. We conclude that both diterpenic labdanes isolated from A. paniculata can exert potent immunosuppressant effects without affecting the viability of the cells.

Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide

“…35) In addition, andrographolide activated apoptosis in human cancer cell lines via activation of caspase-3 and caspase-8 with the participation of mitochondria has been noted. 36,37,62) Recently, andrographolide was reported to possess cytotoxicity to a human oral epidermoid carcinoma cell line. 63) Andrographolide also enhanced production of TNF-α and CD marker expression, resulting in increase of cytotoxic activity of lymphocytes against cancer cells, which may contribute for its indirect anticancer activity.…”

“…10,11) The potent immunosuppressant effects in murine T-cells by significant reduction of IFN-γ production and extracellular-signal-regulated protein kinase (ERK1/2) phosphorylation induced by concanavaline A has been mentioned. 62) The ability of andrographolide to inhibit T cell activation was applied to interfere with the onset of Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory demyelinating disease of the central nervous system that is primarily mediated by CD4(+) T cells and serves as an animal model for human multiple sclerosis. Treatment with andrographolide was able to significantly reduce EAE symptoms in mice by inhibiting T cell and antibody responses directed to myelin antigens.…”

Potential anti-inflammatory bioactives from medicinal plants of Western Ghats, India

“…Eight pure compounds viz., 5-hydroxy-7,8-dimethoxyflavone, 5-hydroxy-7,8-dimethoxyflavanone, a mix of beta-sitosterol and stigmasterol, ergosterol peroxide, 14-deoxy-14,15-dehydroandrographolide, a new compound, 19-O-acetyl-14-deoxy-11,12-didehydroandrographolide, 14-deoxy-11,12-didehydroandrographolide and andrographolide were identified [38] . They were analyzed for anti-inflammatory activity in in vitro studies using RAW 264.7 (Mouse leukaemic monocyte macrophage cell line) stimulated for inflammatory response by LPS/interferon (IFN)-g [39] . A significant decrease in the levels of NFkB mRNA by compounds 5, 11, 12, decreased levels of tumor necrosis factor (TNF)-a, IL-6, MIP-2 and nitric oxide (NO) by all the compounds was recorded.…”

HMPL-004 (Andrographis paniculata extract) Prevents Development of Murine Colitis by Inhibiting T-cell Proliferation and TH1/TH17 Responses

“…Direct effects of andrographolides on T cells have been described in vitro. Concanavaline A-induced IFN-γ and IL-2 production by murine T cells was significantly inhibited by andrographolides by inhibiting extra cellular signal-regulated kinase (ERK)1/2 phosphorylation (15). Interestingly, andrographolides also exhibited anti-apoptotic effects in T cells suggesting that the observed inhibitory effects on cytokine production are not due to cytotoxicity of T cells.…”