Abstract
The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG(35-55)). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients. Coculture of T cells with IL-12 enhanced the secretion of IFN-gamma, but not TNF-alpha, whereas coculture with IL-18 enhanced the secretion of TNF-alpha, but not INF-gamma. However, coculture with both IL-18 and IL-12 induced high levels of both TNF-alpha and IFN-gamma. Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18. Finally, estrogen treatment, previously found to inhibit both TNF-alpha and IFN-gamma production, completely abrogated all signs of passive EAE. These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-gamma/CCR5 and TNF-alpha/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adjuvants, Immunologic / pharmacology*
-
Adoptive Transfer / methods*
-
Amino Acid Sequence
-
Animals
-
Cell Line
-
Culture Media, Conditioned / pharmacology
-
Drug Implants
-
Drug Synergism
-
Encephalomyelitis, Autoimmune, Experimental / immunology*
-
Encephalomyelitis, Autoimmune, Experimental / pathology
-
Encephalomyelitis, Autoimmune, Experimental / prevention & control
-
Epitopes, T-Lymphocyte / immunology
-
Estradiol / administration & dosage
-
Estradiol / pharmacology*
-
Extracellular Space / immunology
-
Extracellular Space / metabolism
-
Female
-
Glycoproteins / antagonists & inhibitors
-
Glycoproteins / immunology
-
Interferon-gamma / antagonists & inhibitors
-
Interferon-gamma / biosynthesis
-
Interleukin-12 / pharmacology*
-
Interleukin-18 / pharmacology*
-
Mice
-
Mice, Inbred C57BL
-
Molecular Sequence Data
-
Myelin-Oligodendrocyte Glycoprotein
-
Peptide Fragments / antagonists & inhibitors
-
Peptide Fragments / immunology
-
Pregnancy Proteins / administration & dosage
-
Pregnancy Proteins / pharmacology
-
Receptors, CCR4
-
Receptors, CCR5 / biosynthesis
-
Receptors, CCR7
-
Receptors, Chemokine / biosynthesis
-
T-Lymphocyte Subsets / immunology
-
T-Lymphocyte Subsets / metabolism
-
T-Lymphocyte Subsets / transplantation*
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors
-
Tumor Necrosis Factor-alpha / biosynthesis
-
Up-Regulation / immunology
Substances
-
Adjuvants, Immunologic
-
Ccr4 protein, mouse
-
Ccr7 protein, mouse
-
Culture Media, Conditioned
-
Drug Implants
-
Epitopes, T-Lymphocyte
-
Glycoproteins
-
Interleukin-18
-
Myelin-Oligodendrocyte Glycoprotein
-
Peptide Fragments
-
Pregnancy Proteins
-
Receptors, CCR4
-
Receptors, CCR5
-
Receptors, CCR7
-
Receptors, Chemokine
-
Tumor Necrosis Factor-alpha
-
myelin oligodendrocyte glycoprotein (35-55)
-
Interleukin-12
-
Estradiol
-
Interferon-gamma