Type of Document	Dissertation
Author	Surace, Michael Joseph
Author's Email Address	SuraceMJ@vt.edu, MikeSurace@gmail.com
URN	etd-04082010-152209
Title	Signaling Cross-Talk Regulating the Expression of Arginase 1 in Murine Macrophages
Degree	PhD
Department	Biology
Advisory Committee	Advisor Name Title Li, Liwu Committee Chair Ehrich, Marion F. Committee Member Lee, Yong Woo Committee Member Schubot, Florian D. Committee Member
Keywords	LPS Lipopolysaccharide ATRA Interleukin 4 IL-4 All-trans Retinoic Acid Arginase Macrophage M2 Alternative
Date of Defense	2010-03-25
Availability	unrestricted
Abstract Macrophages can be activated by a variety of extracellular signals to polarize to either the M1 (inflammatory and antimicrobial) or to the M2 (wound repair and inflammation resolution) phenotype. Expression of arginase 1 in macrophages is a key marker of the M2 phenotype. Arginase 1 expression is induced by interleukin 4 (IL-4), a cytokine secreted by Th2 helper cells. All-trans retinoic acid (ATRA) is a product of metabolism of dietary retinol (vitamin A). In a manner analogous to hormones, ATRA binds to nuclear receptors in cells and influences gene expression and cell physiology. ATRA is important in the resolution of inflammation systemically and on the cellular level, however it has not been linked to M2 activation or arginase 1 expression. Testing the hypothesis that ATRA can induce arginase 1 in macrophages either directly or indirectly, it was found that ATRA alone cannot cause murine bone marrow-derived macrophages (BMDM) to activate in the M2 phenotype (as indicated by arginase 1 expression), however it can dramatically potentiate induction of arginase 1 expression and activity by IL-4. This is the first observation positively linking ATRA to arginase 1. Lipopolysaccharide (LPS), is a conserved structural component of the outer membrane of Gram negative bacteria, and a potent pyrogen. In metabolic endotoxemia, LPS concentration in the blood is slightly elevated, and over the long term this contributes to diverse inflammatory diseases such as atherosclerosis, obesity, and diabetes. LPS promotes the M1 phenotype and suppresses the M2 phenotype, but its contribution at low doses such as those found in metabolic endotoxemia are not well studied. In order to investigate mechanisms of LPS suppression at low doses, mice deficient in IRAK1 and tollip, key mediators or proinflammatory LPS signaling, were used to study IL-4, ATRA, and LPS crosstalk. LPS suppression of arginase 1 was found to be dependent on IRAK1 and tollip, but only at low doses of LPS.
Files	Filename       Size       Approximate Download Time (Hours:Minutes:Seconds)     28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access    Surace_MJ_D_2010.pdf 16.76 Mb 01:17:34 00:39:53 00:34:54 00:17:27 00:01:29

If you have questions or technical problems, please Contact DLA.