title: Cystatin cures visceral leishmaniasis by NF-κB-mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-Tpl2-ERK pathway.
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.
authors.affiliation: Molecular Cell Biology Laboratory, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Kar
authors.forename: Anindita
authors.initials: A
authors.lastname: Ukil
authors.forename: Pijush K
authors.initials: PK
authors.lastname: Das
mesh_terms: D000818:Animals; D015891:Cystatins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005260:Female; D051550:I-kappa B Kinase / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D015891:Cystatins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D051193:Toll-Like Receptors; C073701:Nfkb1 protein, mouse; D007371:Interferon-gamma; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse