Cystatin cures visceral leishmaniasis by NF-κB-mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-Tpl2-ERK pathway

Eur J Immunol. 2011 Jan;41(1):116-27. doi: 10.1002/eji.201040533. Epub 2010 Dec 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystatins / immunology
  • Cystatins / metabolism
  • Cystatins / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / immunology
  • Female
  • I-kappa B Kinase / immunology
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interferon-gamma / therapeutic use
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / enzymology
  • Leishmaniasis, Visceral / immunology
  • MAP Kinase Kinase Kinases / immunology*
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / immunology
  • Macrophages / enzymology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • NF-kappa B p50 Subunit / immunology*
  • NF-kappa B p50 Subunit / metabolism
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins / metabolism
  • Toll-Like Receptors / drug effects
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism

Substances

  • Cystatins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Proto-Oncogene Proteins
  • Toll-Like Receptors
  • Nfkb1 protein, mouse
  • Interferon-gamma
  • Interleukin-1 Receptor-Associated Kinases
  • I-kappa B Kinase
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse