Neutrophils have been considered to be end-differentiated cells that have little or no ability to modulate the inflammatory responses of other cells. More recently, it has become clear that neutrophils release certain cytokines, and that altering neutrophil function or number has profound effects on the systemic inflammatory response induced by endotoxin or sepsis. The mechanisms by which neutrophils modulate inflammatory responses are not well defined but appear to be mediated by more than simple antibacterial or antitoxin effects.Our work is focused on exploring the mechanisms by which neutrophils effect monocyte/macrophage and endothelial cell function. Further, we are collaborating with Dr. Malech (NIAID) to examine these effects in patients with chronic granulomatous disease and in volunteers given granulocyte colony stimulating factor (G-CSF). We have found that production of pro-inflammatory cytokines is downregulated and production of anti-inflammatory cytokines is upregulated in monocytes cocultured with human neutrophils via a mechanism that requires direct cell-to-cell contact (Abstract, Invest Med, 1996). Ex vivo studies using a whole blood tumor necrosis factor assay in G-CSF-stimulated normal volunteers shows that neutrophil number and state of activation has profound effects on cytokine production (Abstract, American Thoracic Society, 1996). Recent work has defined the effects of neutrophils on monocyte production of anti-inflammatory cytokines such as IL-10 and IL-1ra. Current experiments are focusing on the cell surface molecules involved in these responses, and has led to the identification of monoclonal antibodies that interfere with monocyte/neutrophil interactions. Regulation of the inflammatory response by neutrophils may be an important mechanism that represents a potential new therapeutic target for treating sepsis.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL000153-04
Application #
6103569
Study Section
Special Emphasis Panel (CCM)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code