Bruce S. Zwilling

zwilling.1@osu.edu

Professor, Microbiology
Professor, Molecular Virology, Immunology, and Medical Genetics
Professor, Veterinary Biosciences
Ph.D. University of Missouri, 1971.

Mycobacterial resistance, macrophage activation, regulation of macrophage gene expression by corticosteroids and neuroimmunology.

The role of the mononuclear phagocyte in mediating the innate resistance to Mycobacterial growth and as an effector cell responding to signals of the adaptive immune response is the focus of research in my laboratory. Innate resistance to Mycobacterial growth is controlled by a gene termed Nramp1, which codes for a protein called natural resistance associated macrophage protein . Nramp1 has a putative transport protein motif and is found in macrophage phagosomes. We have shown that Nramp1 is an iron transport protein and that the transport of iron into the phagosome stimulates the Fe catalyzed Haber-Weiss reaction resulting in the production of toxic intermediates of oxygen (hydroxyl radicals). The production of the hydroxyl radicals is responsible for the increased resistance mediated by macrophages from Nramp1 wild-type mice. The generation of toxic oxygen intermediates also results in oxidative stress which affects the function of the cells. One effect of oxidative stress results in the stabilization of several mRNA’s of macrophage activation genes. We are studying the mechanism of the oxidative effect on mRNA stability and on gene expression. We are also studying the regulation of Fe transport by macrophages that is mediated by Nramp1.

The function of mononuclear phagocytes is under tight regulatory control and macrophages express receptors for catecholamine and peptide hormones. We have shown that macrophages will respond to catecholamine hormones differently depending on their state of prior activation. The anti-mycobacterial activity of activated macrophages is inhibited by catecholamines via beta-adrenergic stimulation. Binding of the catecholamines to beta receptors inhibits the anti-mycobacterial activity of interferon-gamma activated macrophages as well as the production of reactive nitrogen intermediates. The effect of the catecholamines is mediated by an inhibition of iNOS transcription via the inhibition of NFkB binding to the iNOS promoter. We are investigating how catecholamines regulate the activation of NFkB. Since catecholamines affect the function of operationally defined macrophage populations differently we are also determining if macrophage populations differentially express adrenergic receptors. The activation of macrophages that occurs following alpha adrenergic receptor stimulation is probably mediated by stimulation of Gi coupled receptors. The activation of these pathways and their possible association with murine Toll-like receptors is being investigated.

Lafuse, W.P., R. Alvarez and B.S. Zwilling. 2000. Regulation of Nramp1 mRNA stability by oxidants and protein kinase C in RAW264.7 macrophages expressing Nramp1^Gly169. Biochem. J. 351:687-696.

Wang, T., W.P. Lafuse and B.S. Zwilling. 2000. Regulation of Toll-like receptor 2 expression by macrophages following Mycobacterium avium infection. J. Immunol.165:6308-6313.

D.E. Kuhn, W.P. Lafuse and B.S. Zwilling. Iron transport into Mycobacterium avium containing phagosomes from and Nramp1^Gly169 transfected RAW264.7 macrophage cell line. J. Leuk. Biol. 69: 43-49, 2001.

W-J Zhong, W.P. Lafuse and B.S. Zwilling. Infection with Mycobacterium avium differentially regulates the expression of iron transport protein mRNA in murine peritoneal macrophages. Infect. Immun. 69:6618-6624, 2001.

T. Wang, W.P. Lafuse and B.S. Zwilling. NFB and SP1 elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J. Immunol. 167:6924-6932, 2001.

T. Wang, W.P. Lafuse, K. Takeda, S. Akira and B.S. Zwilling. Rapid chromatin remodeling of TLR2 promoter during infection of macrophages with Mycobacterium avium. J. Immunol. 169:795-801, 2002.

W.P. Lafuse, G.A. Alvarez and B.S. Zwilling. Role of MAP kinase activation in Nramp1 mRNA stability in RAW264.7 macrophages expressing Nramp1^Gly169. Cellular Immunology 215:195-206, 2002.