The role of LTB4 and miRNAs in the regulation of MyD88 expression and activation of NFkB in alveolar macrophages of diabetic rats

• Grant number: 12/13623-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2012
• End date: August 31, 2013
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Sônia Jancar
• Grantee: Luciano Filgueiras Ribeiro Junior
• Supervisor: Carlos Henrique Cardoso Serezani
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Indiana University-Purdue University Indianapolis, United States
• Associated to the scholarship: 10/09388-3 - Molecular and cellular aspects of the lung inflammation caused by sepsis in diabetic and non diabetic rats, BP.DD

Abstract

There is evidence that the leukotrienes (LT)receptors and TLRs may interact during macrophage activation. The inhibition of LT synthesis or the antagonism of its receptors impairs the activation of NFkB in human monocytes and macrophages. Moreover, mice that are deficient of the enzyme 5-lipoxygenase (5-LO) are naturally resistant to LPS-induced multi organs dysfunction. Previous work from our group has shown that the MyD88 dependent response is impaired in mice lacking 5-LO or the high affinity LTB4 receptor, BLT-1. In these mice the activation of NFkB is reduced. This defect in macrophage signaling is associated with a lower basal expression of MyD88 due to a reduced STAT-1 activation and over expression of the STAT-1 inhibitory protein, SOCS-1. Thus LTB4 is essential for STAT-1 dependent MyD88 expression and for MyD88 dependent NFkB activation. Moreover we had shown that during CLP-induced sepsis, diabetic rats develop a milder acute lung injury (ALI) even thought they succumb earlier. The less intense ALI in diabetics correlates with lower expression of the adapter molecule MyD88, over expression of the inhibitory molecule SOCS-1 and impaired activation of NFkB in alveolar macrophages (AMs) of diabetics. So, we propose to investigate the hypothesis that these molecular alterations observed in diabetics AMs are due to a defect on TLR-4 and BLT-1 interaction. Further we pretend to compare the expression of miRNAs in diabetic and non-diabetics and its ability to regulate the TLR-4 expression and its signaling pathways in AMs from diabetics. (AU)