Abstract
Andrographolide is a bicyclic diterpenoid lactone derived from extracts of Andrographis paniculata, a plant indigenous to South Asian countries that shows anti-inflammatory properties. The molecular and cellular bases for this immunomodulatory capacity remain unknown. Here, we show that andrographolide is able to down-modulate both humoral and cellular adaptive immune responses. In vitro, this molecule was able to interfere with T cell proliferation and cytokine release in response to allogenic stimulation. These results were consistent with the observation that T cell activation by dendritic cells (DCs) was completely abolished by exposing DCs to andrographolide during antigen pulse. This molecule was able to interfere with maturation of DCs and with their ability to present antigens to T cells. Furthermore, in vivo immune responses such as antibody response to a thymus-dependent antigen and delayed-type hypersensitivity were drastically diminished in mice by andrographolide treatment. Finally, 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. Our data suggest that andrographolide is able to efficiently block T cell activation in vitro, as well as in vivo, a feature that could be useful for interfering with detrimental T cell responses.
Footnotes
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This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico Grant 1030557, Dirección General de Postgrado, Investigación Grant 2002/11E, Fondo de Investigación en Areas Prioritarias Grant 13980001, and Fondo de Fomento al Desarrollo Científico y Tecnológico Grant DO1I1024. A.M.K. is a Helen Hay Whitney Foundation fellow, C.A.F. is a Comite Nacional de Investigación, Ciencia y Tecnologia fellow, and M.I.I. and J.A.T. are Programa de Mejoramiento de la Calidad y la Equidad de la Educación Superior fellows.
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doi:10.1124/jpet.104.072512.
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ABBREVIATIONS: DC, dendritic cell; APC, antigen-presenting cell; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, mouse myelin oligodendrocyte glycoprotein; PBS, phosphate-buffered saline; OVA, chicken egg ovalbumin; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; NP-BSA, 4-hydroxy-3-nitrophenyl-acetyl conjugated to bovine serum albumin; NP-CGG, 4-hydroxy-3-nitrophenyl-acetyl conjugated to chicken gamma globulin; DTH, delayed-type hypersensitivity.
- Received June 8, 2004.
- Accepted August 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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