Mecanismos inflamatórios envolvidos na indução de febre por lipopolissacarídeo: participação da microbiota comensal, da enzima fosfatidilinositol 3-quinase gama e do receptor do fator ativador de plaquetas

• Ano de defesa: 2015
• Autor(a) principal: Lucas Secchim Ribeiro
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais
• Palavras-chave em Português: Bioquimica; Fosfatidilinositol 3-quinase; Microbiota; Fator ativador de plaquetas; Inflamação; Febre; Fosfatidilinositol 3-quinase gama; Receptor do fator ativador de plaquetas
• Link de acesso: https://hdl.handle.net/1843/BUBD-9ZJG8H

The control of body temperature is thought to contribute to the immune system. In endothermic animals, this modulation is finely tuned by the hypothalamus, with local production of cytokines and lipid mediators. Fever is the hypothalamic response towards the detection of pyrogens either from infectious microorganism or produced by own body during an inflammatory reaction. Nevertheless, fever is a frequently neglected clinical sign, due to its acute and unspecific features. Therefore, the aim of this work is to verify the role of important inflammatory mediators in the development of fever induced by lipopolysaccharide (LPS). To achieve it, we used tools well recognized as important pieces for the inflammation puzzle: a) phosphatidylinositol 3-kinase gamma (PI3K), whose activity is pleiotropic and important for several function, like cell development and gene activation; b) the platelet-activating factor (PAF) and its receptor (PAFR), whose signaling cascade leads to leukocyte activation and cytokine release and c) the commensal microbiota, responsible for priming and maturing the immune system, offering a variety of symbiotic advantages to its host. Our results point that both commensal microbiota as phosphatidylinositol 3-kinase gamma are fundamental for the LPS-induced fever. Their privation leads to the reduction of proinflammatory, pyrogenic cytokines like IL-1 and TNF-. In the central nervous system, this minor peripheral response makes hypothalamus less responsive, with lower expression of cicloxigenase-2, an important enzyme to the production of prostaglandin E2, final mediator of fever in the brain. In other hand, the mice knocked out for the receptor of the platelet-activating factor had a delayed but prolonged fever, in comparison to the wild type mice. This interesting response may be due to higher levels of IL-1 in late times after LPS injection, in a mechanism independent of COX-2 and TNF- expression in the hypothalamus. Taken together, the results suggest that the production of proinflammatory molecules in the periphery is needed for the central hypothalamic response and consequently, the increase in the temperature, as shown in the murine models using germ-free or PI3K KO mice, in which the biological and pharmacological approaches support such hypothesis. On the other hand, the deletion or antagonism of PAF receptor leaded to a unique and equally interesting phenotype. The delay and extension of fever may indicate the role of the lipid mediator in the resolution of febrile process. More detailed studies are required to further explaining the subject, in order to get robust and reliable answers.