Title page for ETD etd-04082010-152209


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.

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