ROLE OF TNF-ALPHA, IL-1, AND IL-1RA IN THE MEDIATION OF LEUKOCYTE INFILTRATION AND INCREASED VASCULAR-PERMEABILITY IN RABBITS WITH LPS-INDUCED PLEURISY

We examined the generation of tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-1 receptor antagonist (IL-1ra), and their role in the mediation of leukocyte infiltration and increased vascular permeability in rabbits with LPS-induced pleurisy. The leukocyte infiltration was largely mediated by both TNF alpha and IL-1 and could be divided into at least two phases: the early (within 3 hr) phase which was partly inhibited by anti-TNF alpha, but not by IL-1ra, and the late phase (4-12 hr) mediated by both TNF alpha and IL-1, and largely inhibited synergistically with anti-TNF alpha and IL-1ra. Endogenous IL-1ra may be responsible for the downregulation of the late phase of leukocyte infiltration in this type of inflammation. The increased vascular permeability was composed of two phases: immediate (15 min) and delayed (2 hr). The immediate permeability was inhibited by H-1,-antihistamine but was not affected by anti-TNF alpha, by IL-1ra, or by depletion of neutrophils. The delayed permeability was completely inhibited by either depletion of neutrophils or by anti-TNF alpha and was not affected by IL-1ra or antihistamine. Production of TNF alpha was maintained in the leukopenic rabbits. It would thus appear that the delayed permeability is mediated by a relatively early fraction of leukocyte infiltration initiated by TNF alpha; however, TNF alpha is not the direct mediator of this delayed permeability. (C) 1995 Academic Press, Inc.