Instituto Butantan

São Paulo, Sao Paulo, Brazil

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Centro de Biotecnologia
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Laboratório de Ecologia e Evolução - LEEV
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Laboratório de Farmacologia
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Publication History View all

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    ABSTRACT: Here we evaluated whether Natterins affect the leukocyte-endothelial cell interaction, hampering leukocyte mobilization and extravasation. Leukocyte-endothelial cell interactions were evaluated in venules of mouse cremaster muscle using intravital microscopy. We reported that low doses of Natterins interfere with the cell capturing, inhibiting the interaction of blood neutrophils with the post-capillary venules induced by the TLR4 agonist LPS, or the chemokine KC. Using endotoxemic mice challenged with LPS, we confirmed that Natterins reduce neutrophil accumulation in the peritoneum exudates. The rolling of leukocytes induced by KC or LPS was not impaired in Natterins-treated TLR2, MyD88 deficient or TLR4 mutant mice, indicating that TLR2- or TLR4-MyD88-mediated signals are required for the anti-inflammatory effect of Natterins. The inhibitory effect was not influenced by endogenous regulators of inflammation such as IL-10, corticosteroids, the HO-1 or the antagonist of the receptor of IL-1, nor by the disruption of their proteolytic activity. However, it was completely dependent on the activation of serine/threonine phosphatases and the PI3K signaling pathway, but independent on increased proteasome activity. This work started asking how the main toxins in the T nattereri venom contributes for the deficient influx of inflammatory leukocytes, which consequently drive to the delayed inflammatory reaction finalization in injured tissue; and finished demonstrating that Natterins can control the leukocyte-endothelial wall interactions in a mechanism dependent on negative signals derived from TLR2-TLR4/Myd88 signaling cascade. Interestingly, we confirmed that the antagonist effect of Natterins is mediated by the activation of serine/threonine phosphatases and by the key signaling PI3K molecule.
    Toxicon 01/2014;
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    ABSTRACT: Components of high molecular-weight (PI) obtained from Ascaris suum extract down-regulate the Th1/Th2-related immune responses induced by ovalbumin (OVA)-immunization in mice. Furthermore, the PI down-modulates the ability of dendritic cells (DCs) to activate T lymphocytes by an IL-10-mediated mechanism. Here, we evaluated the role of toll like receptors 2 and 4 (TLR2 and 4) in the modulatory effect of PI on OVA-specific immune response and the PI interference on DC full activation. An inhibition of OVA-specific cellular and humoral responses were observed in wild type (WT) or in deficient in TLR2 (TLR2(-/-)) or 4 (TLR4(-/-)) mice immunized with OVA plus PI when compared with OVA-immunized mice. Low expression of class II MHC, CD40, CD80 and CD86 molecules was observed in lymph node (LN) cells from WT, TLR2(-/-) or TLR4(-/-) mice immunized with OVA plus PI compared with OVA-primed cells. We also verified that PI was able to modulate the activation of DCs derived from bone marrow of WT, TLR2(-/-) or TLR4(-/-) mice induced in vitro by agonists of TLRs, as observed by a decreased expression of class II MHC and costimulatory molecules and by low secretion of pro-inflammatory cytokines. Its effect was accompanied by IL-10 synthesis. In this sense, the modulatory effect of PI on specific-immune response and DC activation is independent of TLR2 or TLR4.
    Molecular Immunology 11/2013; 58(1):17-26.
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    ABSTRACT: This work shows the production and characterization of two novel putative lipoproteins encoded by the genes LIC10645 and LIC10731, identified in the genome sequences of L. interrogans. In silico conservation analysis indicate that the proteins are well conserved among pathogenic leptospiral serovars and species. Recombinant proteins were obtained in E. coli BL21 (DE3) Star pLysS strain, purified by metal-affinity chromatography and used for characterization and immunological evaluations. Recombinant proteins are capable of eliciting a combination of humoral and cellular immune response in animal model and could be recognized by antibodies present in human serum samples. The recombinant proteins LIC10645 and LIC10731 are able to bind laminin and were named, Lsa44 and Lsa45, for leptospiral surface adhesins of 44 and 45 kDa, respectively. The attachment to laminin was dose-response with a KD value of 108.21 and 250.38 nM for Lsa44 and Lsa45, respectively. Moreover, these proteins interact with plasminogen (PLG) with a KD value of 53.56 and 36.80 nM, respectively. PLG bound to the recombinant proteins could be converted to plasmin in the presence of an activator. Cellular localization assays suggest that the proteins LIC10645 and LIC10731 are surface-exposed. These are versatile proteins able of interacting to laminin and PLG/PLA and hence, could mediate bacterial adhesion and contribute to tissue penetration.
    Microbiology 10/2013;


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    Av. Vital Brazil, 1500, 05503-900, São Paulo, Sao Paulo, Brazil
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