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

Das, Pijush K. ; Kar, Susanta ; Ukil, Anindita (2011) Cystatin cures visceral leishmaniasis by NF-κB mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-Tpl2-ERK pathway European Journal of Immunology, 14 . pp. 116-127. ISSN 0014-2980

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Official URL: http://onlinelibrary.wiley.com/doi/10.1002/eji.201...

Related URL: http://dx.doi.org/10.1002/eji.201040533

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.

Item Type:Article
Source:Copyright of this article belongs to John Wiley and Sons, Inc.
Keywords:Leishmaniasis; Macrophage; Cystatin; Nuclear Factor-κB; Tumor Progression Locus 2
ID Code:30470
Deposited On:23 Dec 2010 13:30
Last Modified:17 May 2016 13:06

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