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Modulation by natterins of the endothelial cell activation induced by the TLR4 agonist

Grant number: 13/12590-7
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2013
Effective date (End): December 31, 2014
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Monica Valdyrce dos Anjos Lopes Ferreira
Grantee:Carolina Manganeli Polonio
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Studies developed previously by our group show that the venom of Thalassophryne nattereri venomous fish develops an inappropriate cellular inflammatory response characterized by a reduced number of leukocytes at the site of injury. Combined proteomic and transcriptomic approaches to study the composition of the venom of Thalassophryne nattereri venomous fish revealed the primary structures of the major toxins as a family of proteases Natterins, never described on venoms and a C-type lectin Nattectin. Recently we described that the treatment of mice with Natterins reduces the leukocytes rolling induced by KC at 30 min of observation and that this reduction has no correlation with the protease activity of Natterins on KC. However, Natterins were unable to inhibit the leukocyte rolling induced by agPAR-4 indicating that this receptor is not affected by Natterins. Next, we evaluated the inhibitory effect of Natterins in the leukocyte rolling induced by KC using TLR2 KO or TLR4 mutant mice and we found that the inhibitory effect of Natterins is dependent on the expression of both receptors. These data were also similar in the studies of cell migration into the peritoneal cavity. When rolling behavior was determined after topical application of LPS in mice pre-treated with Natterins, the proportions of rolling leukocytes in venules were almost the same in control-mice; and the inhibitory effect was independent of this protease activity and totally dependent on the TLR2 and MyD88 expression, reinforcing the involvement of TLR receptors in this process. Natterins inhibitory effect was not influenced by endogenous regulators of inflammation such as IL-10, corticosteroids, the heme oxygenase-1 (HO-1), or IL-1 receptor antagonist (IL-1Ra), however, its inhibitory effect is completely dependent on the PI3K signaling pathway and the action of protein serine/threonine phosphatases. Together, these data demonstrate that the inhibitory effect of Natterins seems to be dependent of TLR/MyD88 and PI3K signaling pathways activation and protein serine/threonine phosphatases, and support the inhibitory capacity of the Natterins in acute and systemic inflammatory processes. The aim of this project is the understanding the mechanism of action involved in the antagonist effect of Natterins in endothelial cells. (AU)

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