Medical Science Building (MSB) 185 South Orange Avenue Room MSB G677 Newark, NJ 07101 Phone: (973) 972-5404 Fax: (973) 972-7489
Ph.D., 1971, University of Manchester B.Sc., 1968, University of Manchester, Manchester, England
NEMETH, Z.H., LEIBOVICH, S.J., DEITCH, E.A., SPERLAGH, B., VIRAG, L., VIZI, E.S., SZABO, C., HASKO, G. Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism. Biochem. Biophys. Res. Comms. 312, 2003, 883-888.
NEMETH, Z.H., LEIBOVICH, S.J., DEITCH, E.A., VIZI, E.S., SZABO, C., HASKO, G. cDNA microarray analysis reveals a nuclear factor-?B-independent regulation of macrophage function by adenosine. J. Pharmacol. Exp. Therapeut. 306, 2003, 1042-1049.
PINHAL-ENFIELD, G., RAMANATHAN, HASKO, G., VOGEL, S.N., SALZMAN, A.L., BOONS, G.J. AND LEIBOVICH, S.J. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7 and 9 and adenosine A2A receptors. Am. J. Pathol. 163, 2003, 711-721.
RAMANTHAN, M., GILADI, A. AND LEIBOVICH, S.J. Regulation of VEGF gene expression in murine macrophages by nitric oxide and hypoxia. Exp. Cell Biol. 228, 697-705, 2003.
LEIBOVICH, S.J., CHEN, J.F., PINHAL-ENFIELD, G., BELEM, P., ELSON, G., ROSANIA, A., RAMANATHAN, M., MONTESINOS, C., JACOBSON, M., SCHWARTZSCHILD M.A., FINK, S.J., AND CRONSTEIN, B. Synergistic Up-Regulation of Vascular Endothelial Growth Factor Expression in Murine Macrophages by Adenosine A2A Receptor Agonists and Endotoxin . Am. J. Pathol. 160, 2231-2244, 2002.
XIONG, M., ELSON, E., LEGARDA, D and LEIBOVICH, S.J. Production of vascular endothelial growth factor (VEGF) by murine macrophages; Regulation by hypoxia, lactate and the inducible nitric oxide-synthase pathway. Am. J. Pathol. 153, 587-598, 1998.
POLVERINI, P.J. and LEIBOVICH, S.J. Effect of macrophage depletion on growth and neovascularization of hamster buccal pouch carcinomas. J. Oral Pathol. 16:436, 1987.
GABIZON, A., LEIBOVICH, S.J. and GOLDMAN, R. Contrasting effects of activated and non-activated macrophages and macrophages from tumor bearing mice on tumor growth in vivo. J. Nat'l. Canc. Inst. 65:913,1980.
Macrophages are an important cell type involved in inflammation, wound healing and solid tumor development. We are investigating the mechanisms involved in the regulation of expression of angiogenic activity by macrophages, and the role that these pathways play in the regulation of angiogenesis in wound healing, inflammation and cancer development. We have defined three pathways in macrophages that regulate expression of VEGF. The first involves hypoxia; the second involves nitric oxide (NO); the third involves a novel interaction between adenosine A2A receptors and Toll-like receptors (TLRs). We are analyzing the elements in the 5' promoter of the VEGF gene that are involved in hypoxic and NO-dependent transcriptional regulation of VEGF expression. We are also analyzing the elements in the 3' UTR of the VEGF gene involved in the regulation of VEGF mRNA stability. The synergistic interaction between adenosine A2A receptors and TLRs results in strong up-regulation of VEGF expression, and we are analyzing the signal transduction pathways involved in this novel interaction. These studies involve analyses of both TLR signaling and adenosine receptor signaling. We have recently found that activation of macrophages involves the regulation of expression of subsets of miRNAs that regulate the stability of select macrophage products. We are studying the role of epigenetic regulation of macrophage gene expression, in particular the involvement of chromatin modifying enzymes of the histone acetyl transferase (HAT) family.
We are also examining the role of the novel signaling pathways that we have discovered in macrophages in the regulation of tumor growth. These studies may provide novel modalities for therapeutic intervention in both wound healing and tumor development by interfering with the pathways that regulate expression of iknflammatory and angiogenic factors.