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Analysis of upstream signaling events revealed that TLR 2\/4\u2010mediated MyD88\u2010dependent participation of IL\u20101R\u2010activated kinase (IRAK)1, TNF receptor\u2010associated factor (TRAF)6 and TGF\u03b2\u2010activated kinase (TAK)1 is essential to induce cystatin\u2010mediated I\u03baB kinase (IKK)\/NF\u2010\u03baB activation in macrophages. Cystatin plus IFN\u2010\u03b3 activated the IKK complex to induce phosphorylation\u2010mediated degradation of p105, the physiological partner and inhibitor of the MEK kinase, tumor progression locus 2 (Tpl\u20102). Consequently, Tpl\u20102 was liberated from p105, thereby stimulating activation of the MEK\/ERK MAPK cascade. Cystatin plus IFN\u2010\u03b3\u2010induced IKK\u2010\u03b2 post\u2010transcriptionally modified p65\/RelA subunit of NF\u2010\u03baB by dual phosphorylation in infected phagocytic cells. IKK induced the phosphorylation of p65 directly on Ser\u2010536 residue whereas phosphorylation on Ser 276 residue was by sequential activation of Tpl\u20102\/MEK\/ERK\/MSK1. Collectively, the present study indicates that cystatin plus IFN\u2010\u03b3\u2010induced MyD88 signaling may bifurcate at the level of IKK, leading to a divergent pathway regulating NF\u2010\u03baB activation by I\u03baB\u03b1 phosphorylation and by p65 transactivation through Tpl\u20102\/MEK\/ERK\/MSK1.<\/jats:p>","DOI":"10.1002\/eji.201040533","type":"journal-article","created":{"date-parts":[[2010,10,27]],"date-time":"2010-10-27T08:11:25Z","timestamp":1288167085000},"page":"116-127","source":"Crossref","is-referenced-by-count":34,"title":["Cystatin cures visceral leishmaniasis by NF\u2010\u03baB\u2010mediated proinflammatory response through co\u2010ordination of TLR\/MyD88 signaling with p105\u2010Tpl2\u2010ERK 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