Abstract
Blockade of TNF-related activation-induced cytokine (TRANCE)-receptor activator of NF-kappaB (RANK) interaction reverses healing in CD40L(-/-) mice infected with Leishmania major. Although previous studies demonstrated a requirement for CD40-CD40L interaction in production of IL-12 and the development of resistance to Leishmania infection, we recently showed that CD40L(-/-) mice control infection when inoculated with low numbers of parasites and that cells from these mice produce IL-12. Here, we show that in vivo treatment with a TRANCE receptor fusion protein results in a decrease in numbers of IL-12 producing cells as well as a shift from a dominant Th1 to Th2 type response in infected mice. These results demonstrate that CD40L(-/-) mice use the TRANCE-RANK costimulatory pathway to promote IL-12 production and the activation of a protective Th1 type response.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD40 Ligand / genetics*
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cells, Cultured
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Down-Regulation / immunology
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Female
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Glycoproteins / antagonists & inhibitors
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Glycoproteins / metabolism
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Glycoproteins / physiology*
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Humans
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / genetics
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Immunophenotyping
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis*
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Leishmania major / growth & development
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Leishmania major / immunology*
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Leishmaniasis, Cutaneous / genetics
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Leishmaniasis, Cutaneous / immunology*
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Leishmaniasis, Cutaneous / parasitology
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Leishmaniasis, Cutaneous / pathology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology*
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Receptors, Tumor Necrosis Factor / administration & dosage
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Receptors, Tumor Necrosis Factor / genetics
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Recombinant Fusion Proteins / administration & dosage
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Signal Transduction / genetics
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Signal Transduction / immunology
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Th1 Cells / immunology*
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Th1 Cells / metabolism*
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Th1 Cells / parasitology
Substances
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Carrier Proteins
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Glycoproteins
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Immunoglobulin Fc Fragments
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Membrane Glycoproteins
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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CD40 Ligand
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Interleukin-12