Abstract
Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Because dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance, we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize self-peptide-major histocompatibility complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor nuclear factor (NF)-κB. We evaluated the capacity of drugs that inhibit NF-κB to enhance the tolerogenic properties of immature DCs in the experimental autoimmune encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, were able to interfere with NF-κB activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-κB-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-κB blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.
Footnotes
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This work was supported by Fondo Nacional de Cientifico y Tecnologico Grants 1030557 (to A.M.K.), 1030617 (to M.A.G. and S.H.J.), and 1050979 (to S.H.J., A.M.K., and M.A.G.); by International Foundation for Science Grant A/3639-1 (to A.M.K.); by Fondo de Investigacion en Areas Prioritarias Grant 13980001 (to M.B. and A.M.K.); and by Millennium Nucleus on Immunology and Immunotherapy (to A.M.K.). M.I.I. is a Mejoramiento de la Calidad y la Equidad de la Educación Superior fellow.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.103259.
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ABBREVIATIONS: DC, dendritic cell; NF, nuclear factor; LPS, lipopolysaccharide; PPAR, peroxisome proliferator-activated receptor; EAE, experimental autoimmune encephalomyelitis; MHC, major histocompatibility complex; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; MOG, myelin oligodendrocyte glycoprotein; OVA, ovalbumin; FITC, fluorescein isothiocyanate; FACS, fluorescence-activated cell sorting; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; IFN, interferon; PCR, polymerase chain reaction; CFA, complete Freund's adjuvant; DTH, delayed-type hypersensibility.
- Received February 21, 2006.
- Accepted April 4, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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