Until recently, neutrophils have been considered to be end- differentiated cells that provide a first line of defense against invading microorganisms. They were considered to have little or no ability to modulate the inflammatory responses of other cells. Now it has become clear that neutrophils release certain cytokines and that altering neutrophil function or number profoundly affects 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 focuses on exploring the mechanisms by which neutrophils affect monocyte/macrophage and endothelial cell function. Further, we are collaborating with Dr. Malech at the National Institute of Allergy and Infectious Disease to examine these effects in patients with chronic granulomatous disease and in volunteers given granulocyte colony-stimulating factor (G-CSF). We have found that neutrophils down-regulate cytokine production by other cells through a mechanism that requires direct cell-to-cell contact. Under other conditions, neutrophils up-regulate cytokine production through secretion of a soluble factor (Baram, D. et.al., Journal of Investigative Medicine, 44(3), 277A, 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 have profound effects on cytokine production (Abstract, American Thoracic Society, 1996). The regulation of the inflam-matory response by neutrophils may be an important mechanism that represents a potential new therapeutic target for treating sepsis.
