Philip E. Hass

Modulation of the growth of human and murine cell lines in vitro by recombinant human tumor necrosis factor-alpha (rTNF-alpha) and recombinant human interferon-gamma (rIFN-gamma) was investigated. rTNF-alpha had cytostatic or cytolytic effects on only some tumor cell lines. When administered together with rIFN-gamma, rTNF-alpha showed enhanced antiproliferative effects on a subset of the cell lines tested. In contrast to its effects on sensitive tumor cells, rTNF-alpha augmented the growth of normal diploid fibroblasts. Variations in the proliferative response induced by rTNF-alpha were apparently not due to differences in either the number of binding sites per cell or their affinity for rTNF-alpha. These observations indicate that the effects of rTNF-alpha on cell growth are not limited to tumor cells, but rather that this protein may have a broad spectrum of activities in vivo.

Certain inflammatory stimuli render cultured human vascular endothelial cells hyperadhesive for neutrophils. This state is transient and reversible, in part because activated endothelial cells secrete a leukocyte adhesion inhibitor (LAI). LAI was identified as endothelial interleukin-8 (IL-8), the predominant species of which is an extended amino-terminal IL-8 variant. At nanomolar concentrations, purified endothelial IL-8 and recombinant human IL-8 inhibit neutrophil adhesion to cytokine-activated endothelial monolayers and protect these monolayers from neutrophil-mediated damage. These findings suggest that endothelial-derived IL-8 may function to attenuate inflammatory events at the interface between vessel wall and blood.