Abstract

We have been interested in the mechanisms of host defense against neoplastic cells. When macrophages are stimulated with bacterial lipopolysaccharide (LPS), they become highly cytotoxic to a variety of neoplastic cells. In order to understand the molecular mechanisms involved in this process, we plan to (l) characterize the LPS-responsive elements (LRE) in promoter regions of the immediate early genes transcriptionally activated by LPS, (2) characterize and isolate transcription factor(s) that become associated with LRE and (3) isolate the gene called lps that controls the responsiveness of mouse and murine macrophages to LPS. The responses of macrophages to LPS stimulation can occur without the participation of T or B lymphocytes, and may very well represent a primitive defense reaction against potential pathogens. Elucidation of molecular mechanisms involved in this process will advance our understanding of septic shock caused by LPS, action of anticancer drug Taxol, as well as natural immunity against a variety of potentially harmful agents including virus and neoplastic cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA014113-24
Application #
2712526
Study Section
Immunobiology Study Section (IMB)
Program Officer
Finerty, John F
Project Start
1978-08-01
Project End
2001-05-31
Budget Start
1998-08-10
Budget End
2001-05-31
Support Year
24
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Noble, P W; McKee, C M; Cowman, M et al. (1996) Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages. J Exp Med 183:2373-8
Lokuta, M A; Maher, J; Noe, K H et al. (1996) Mechanisms of murine RANTES chemokine gene induction by Newcastle disease virus. J Biol Chem 271:13731-8
Shin, H S; Drysdale, B E; Shin, M L et al. (1994) Definition of a lipopolysaccharide-responsive element in the 5'-flanking regions of MuRantes and crg-2. Mol Cell Biol 14:2914-25
Symer, D E; Paznekas, W A; Shin, H S (1993) A requirement for membrane-associated phospholipase A2 in platelet cytotoxicity activated by receptors for immunoglobulin G and complement. J Exp Med 177:937-47
Nishijima, J; Wright, T M; Hoffman, R D et al. (1989) Lysophosphatidylcholine metabolism to 1,2-diacylglycerol in lymphoblasts: involvement of a phosphatidylcholine-hydrolyzing phospholipase C. Biochemistry 28:2902-9
Wagner, J E; Johnson, R J; Santos, G W et al. (1989) Systemic monoclonal antibody therapy for eliminating minimal residual leukemia in a rat bone marrow transplant model. Blood 73:614-8
Wright, T M; Hoffman, R D; Nishijima, J et al. (1988) Leukocyte chemoattraction by 1,2-diacylglycerol. Proc Natl Acad Sci U S A 85:1869-73
Drysdale, B E; Agarwal, S; Shin, H S (1988) Macrophage-mediated tumoricidal activity: mechanisms of activation and cytotoxicity. Prog Allergy 40:111-61
Agarwal, S; Drysdale, B E; Shin, H S (1988) Tumor necrosis factor-mediated cytotoxicity involves ADP-ribosylation. J Immunol 140:4187-92
Drysdale, B E; Yapundich, R A; Shin, M L et al. (1987) Lipopolysaccharide-mediated macrophage activation: the role of calcium in the generation of tumoricidal activity. J Immunol 138:951-6

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