Signaling Cross-Talk Regulating the Expression of Arginase 1 in Murine Macrophages

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dc.contributor.authorSurace, Michael Josephen
dc.contributor.committeechairLi, Liwuen
dc.contributor.committeememberEhrich, Marion F.en
dc.contributor.committeememberLee, Yong Wooen
dc.contributor.committeememberSchubot, Florian D.en
dc.contributor.departmentBiologyen
dc.date.accessioned2014-03-14T20:09:07Zen
dc.date.adate2010-04-23en
dc.date.available2014-03-14T20:09:07Zen
dc.date.issued2010-03-25en
dc.date.rdate2010-04-23en
dc.date.sdate2010-04-08en
dc.description.abstractMacrophages 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 deficient 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.en
dc.description.degreePh. D.en
dc.identifier.otheretd-04082010-152209en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-04082010-152209/en
dc.identifier.urihttp://hdl.handle.net/10919/26704en
dc.publisherVirginia Techen
dc.relation.haspartSurace_MJ_D_2010.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectLPSen
dc.subjectLipopolysaccharideen
dc.subjectATRAen
dc.subjectInterleukin 4en
dc.subjectIL-4en
dc.subjectAll-trans Retinoic Aciden
dc.subjectArginaseen
dc.subjectMacrophageen
dc.subjectM2en
dc.subjectAlternativeen
dc.titleSignaling Cross-Talk Regulating the Expression of Arginase 1 in Murine Macrophagesen
dc.typeDissertationen
thesis.degree.disciplineBiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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