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

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Title Cystatin Cures Visceral Leishmaniasis by NF-jBmediated
Proinflammatory Response through
Co-ordination of TLR/MyD88 Signaling
with p105-Tpl2-ERK Pathway
 
Creator Kar, Susanta
Ukil, Anindita
Das, Pijush K
 
Subject Infectious Diseases and Immunology
 
Description 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.
 
Publisher John Wiley & Sons
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/97/1/EUROPEAN_JOURNAL_OF_IMMUNOLOGY%2C_41(1)_116%2D127%2C2011[109].pdf
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
 
Relation http://dx.doi.org/10.1002/eji.201040533
http://www.eprints.iicb.res.in/97/