Cystatin Cures Visceral Leishmaniasis by NF-jBmediated Proinflammatory Response through Co-ordination of TLR/MyD88 Signaling with p105-Tpl2-ERK Pathway

Kar, Susanta and Ukil, Anindita and Das, Pijush K (2011) Cystatin Cures Visceral Leishmaniasis by NF-jBmediated Proinflammatory Response through Co-ordination of TLR/MyD88 Signaling with p105-Tpl2-ERK Pathway. European Journal of Immunology, 41. pp. 116-127. ISSN 0014-2980

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    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-jB 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 TGFb-activated kinase (TAK)1 is essential to induce cystatin-mediated IjB kinase (IKK)/NF-jB activation in macrophages. Cystatin plus IFN-c 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-c-induced IKK-b post-transcriptionally modified p65/RelA subunit of NF-jB 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-c-induced MyD88 signaling may bifurcate at the level of IKK, leading to a divergent pathway regulating NF-jB activation by IjBa phosphorylation and by p65 transactivation through Tpl-2/MEK/ERK/MSK1.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/97
    Subjects: Infectious Diseases and Immunology
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 28 Sep 2011 15:20
    Last Modified: 22 Jan 2013 15:22
    Official URL: http://dx.doi.org/10.1002/eji.201040533
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