Abstract

The role of inflammation in promotion of tumor development in response to chemical carcinogens is important but incompletely understood. One current hypothesis is that leukocytes when stimulated with phorbol esters release free radicals which may cause genomic changes. We have found that the release of reactive oxygen intermediates (ROI) from macrophages is regulated at multiple molecular levels and that model xenobiotics can alter the release of ROI. We have further established that macrophages can initiate DNA damage in cocultivated eukaryotic cells. We here propose to analyze in molecular terms how the potential for secretion of ROI is altered in macrophages from animals exposed to model xenobiotics; to define the precise conditions under which macrophages cause alterations in DNA in cocultivated cells; and to establish the role of ROI and other compounds such as lipid peroxides in DNA damage. Our long range goal is to study the role of macrophages and their secreted products in potentiating chemical carcinogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002922-07
Application #
3250146
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1982-06-01
Project End
1990-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Misra, U K; Shackelford, R E; Florine-Casteel, K et al. (1996) Maleylated-BSA induces hydrolysis of PIP2, fluxes of Ca2+, NF-kappaB binding, and transcription of the TNF-alpha gene in murine macrophages. J Leukoc Biol 60:784-92
Schackelford, R E; Misra, U K; Florine-Casteel, K et al. (1995) Oxidized low density lipoprotein suppresses activation of NF kappa B in macrophages via a pertussis toxin-sensitive signaling mechanism. J Biol Chem 270:3475-8
Adams, D O (1994) Molecular biology of macrophage activation: a pathway whereby psychosocial factors can potentially affect health. Psychosom Med 56:316-27
Melhus, O; Koerner, T J; Adams, D O (1991) Effects of TNF alpha on the expression of class II MHC molecules in macrophages induced by IFN gamma: evidence for suppression at the level of transcription. J Leukoc Biol 49:21-8
Fan, S; Fehr, H G; Adams, D (1991) Activation of macrophages for ADCC in vitro: effects of IL-4, TNF, interferons-alpha/beta, interferon-gamma, and GM-CSF. Cell Immunol 135:78-87
Sebaldt, R J; Prpic, V; Hollenbach, P W et al. (1990) IFN-gamma potentiates the accumulation of diacylglycerol in murine macrophages. J Immunol 145:684-9
Figueiredo, F; Uhing, R J; Okonogi, K et al. (1990) Activation of the cAMP cascade inhibits an early event involved in murine macrophage Ia expression. J Biol Chem 265:12317-23
Figueiredo, F; Koerner, T J; Adams, D O (1989) Molecular mechanisms regulating the expression of class II histocompatibility molecules on macrophages. Effects of inductive and suppressive signals on gene transcription. J Immunol 143:3781-6
Uhing, R J; Prpic, V; Hollenbach, P W et al. (1989) Involvement of protein kinase C in platelet-activating factor-stimulated diacylglycerol accumulation in murine peritoneal macrophages. J Biol Chem 264:9224-30
Uhing, R J; Adams, D O (1989) Molecular events in the activation of murine macrophages. Agents Actions 26:9-14

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