Microvascular plasma protein leakage is an essential component of the inflammatory
response and serves an important function in local host defense and tissue repair. Mediators
such as histamine and bradykinin act directly on venules to increase the permeability
of endothelial cell (EC) junctions. Neutrophil chemoattractants also induce leakage, a
response that is dependent on neutrophil adhesion to ECs, but the underlying mechanism
has proved elusive. Through application of confocal intravital microscopy to the mouse
cremaster muscle, we show that neutrophils responding to chemoattractants release TNF
when in close proximity of EC junctions. In vitro, neutrophils adherent to ICAM-1 or ICAM-2
rapidly released TNF in response to LTB4, C5a, and KC. Further, in TNFR/ mice, neutrophils
accumulated normally in response to chemoattractants administered to the cremaster
muscle or dorsal skin, but neutrophil-dependent plasma protein leakage was abolished.
Similar results were obtained in chimeric mice deficient in leukocyte TNF. A locally injected
TNF blocking antibody was also able to inhibit neutrophil-dependent plasma leakage, but
had no effect on the response induced by bradykinin. The results suggest that TNF mediates
neutrophil-dependent microvascular leakage. This mechanism may contribute to the effects
of TNF inhibitors in inflammatory diseases and indicates possible applications in lifethreatening
acute edema.