Abstract
Cystatin could completely cure experimental visceral leishmaniasis by switching the differentiation of Th2 cells to Th1 type, as well as upregulating NO, and activation of NF-κB played a major role in these processes. Analysis of upstream signaling events revealed that TLR 2/4-mediated MyD88-dependent participation of IL-1R-activated kinase (IRAK)1, TNF receptor-associated factor (TRAF)6 and TGFβ-activated kinase (TAK)1 is essential to induce cystatin-mediated IκB kinase (IKK)/NF-κB activation in macrophages. Cystatin plus IFN-γ activated the IKK complex to induce phosphorylation-mediated degradation of p105, the physiological partner and inhibitor of the MEK kinase, tumor progression locus 2 (Tpl-2). Consequently, Tpl-2 was liberated from p105, thereby stimulating activation of the MEK/ERK MAPK cascade. Cystatin plus IFN-γ-induced IKK-β post-transcriptionally modified p65/RelA subunit of NF-κB by dual phosphorylation in infected phagocytic cells. IKK induced the phosphorylation of p65 directly on Ser-536 residue whereas phosphorylation on Ser 276 residue was by sequential activation of Tpl-2/MEK/ERK/MSK1. Collectively, the present study indicates that cystatin plus IFN-γ-induced MyD88 signaling may bifurcate at the level of IKK, leading to a divergent pathway regulating NF-κB activation by IκBα phosphorylation and by p65 transactivation through Tpl-2/MEK/ERK/MSK1.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cystatins / immunology
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Cystatins / metabolism
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Cystatins / therapeutic use*
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Extracellular Signal-Regulated MAP Kinases / immunology
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Female
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I-kappa B Kinase / immunology
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Inflammation / drug therapy*
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Inflammation / enzymology
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Inflammation / immunology
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interferon-gamma / therapeutic use
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Interleukin-1 Receptor-Associated Kinases / immunology
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Leishmaniasis, Visceral / drug therapy*
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Leishmaniasis, Visceral / enzymology
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Leishmaniasis, Visceral / immunology
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MAP Kinase Kinase Kinases / immunology*
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MAP Kinase Kinase Kinases / metabolism
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MAP Kinase Signaling System / immunology
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Macrophages / enzymology
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Macrophages / immunology
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Mice
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Mice, Inbred BALB C
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / immunology*
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NF-kappa B / metabolism
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NF-kappa B p50 Subunit / immunology*
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NF-kappa B p50 Subunit / metabolism
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Proto-Oncogene Proteins / immunology*
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Proto-Oncogene Proteins / metabolism
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Toll-Like Receptors / drug effects
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
Substances
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Cystatins
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Myeloid Differentiation Factor 88
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NF-kappa B
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins
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Toll-Like Receptors
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Nfkb1 protein, mouse
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Interferon-gamma
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Interleukin-1 Receptor-Associated Kinases
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I-kappa B Kinase
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase Kinases
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Map3k8 protein, mouse