The lipopolysaccharide (LPS) endotoxins of Gram-negative bacteria are molecules that have a great affinity for mammalian cells. The results of this interaction are multiple pathophysiological and immunological responses by the host. Indeed, the estimated thousands of cases of septic shock that occur each year are believed to be a result of endotoxemia caused by the systemic invasion of Gram-negative bacteria. At the cellular level, endotoxins have been shown to polyclonally activate the antibody producing B-lymphocytes. Our long term objective has been to gain a better understanding of how endotoxin affects cells and in particular how B-lymphocytes are activated. In this regard the genetically deficient, endotoxin non-responder C3H/HeJ mouse strain is a very useful model. Recently, it has been found that the B-lymphocytes of this mouse are suppressed from being activated by smooth-type LPSs. This inhibition occurs after the cells have been stimulated by appropriate mitogens. As a consequence, the non-responder cells may be responding to the LPS but in a negative fashion. We intend to investigate this novel phenomenon by: (1) defining which of the individual components of the LPS may be the active inhibitor using hydrolytic separation techniques; (2) determining the binding characteristics of the inhibitory LPS for C3H/HeJ B-cells using radiolabelled LPS; (3) determining whether the suppression extends to C3H/HeJ macrophages using Interleukin-1 production as a measure of macrophage activity; and (4) analyzing cell cycle events that may be directly affected by the suppression including changes in RNA metabolism, membrane potentials and the activation of serine proteases known to be related to the commitment of B-cells to proliferation. In this manner, it is anticipated that new information will be obtained about the mechanism(s) of endotoxin interaction with cells and the consequent effects on the host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028526-03
Application #
3143089
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1989-08-01
Project End
1994-01-31
Budget Start
1991-08-01
Budget End
1994-01-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Abu-Lawi, K I; Sultzer, B M (1995) Induction of serine and threonine protein phosphorylation by endotoxin-associated protein in murine resident peritoneal macrophages. Infect Immun 63:498-502
Abu-Lawi, K I; Sultzer, B M (1994) Differing signal requirements for the activation of macrophages from C3H/HeJ and C3H/OuJ mice. FEMS Immunol Med Microbiol 10:31-8
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