EFFECT OF SOLUBLE P55 TUMOR-NECROSIS-FACTOR BINDING FUSION PROTEIN ONTHE LOCAL SHWARTZMAN AND ARTHUS REACTIONS

1 In this study, the effects of a protein synthesis inhibitor, cyclohe ximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55-sf2 on the priming and challenge stages of the local Shwa rtzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour n ecrosis factor-alpha (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin. 2 The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followe d by two i.v. challenge injections 20 h and 22 h later. Accumulation o f Cr-51-labelled red blood cells and [I-125]-albumin were measured at 24 h as markers of haemorrhage and oedema formation, respectively. 3 T he RPA reaction was induced in the rabbit by giving i.d. injections of Arthus anti-serum (anti-bovine-gamma-globulin, EGG) followed 5 min la ter by an i.v. injection of the antigen (EGG). Oedema formation and th e accumulation of In-111-labelled neutrophils produced in the RPA reac tion and in response to i.d. injection of rhTNF and LPS were measured over the 4 h period after inducing the responses. 4 A single local inj ection of cycloheximide (10 mu g/site) did not inhibit neutrophil accu mulation or oedema formation produced by 100% Arthus anti-sera. Althou gh LPS injected i.d. induced a marked dose-dependent neutrophil accumu lation, there was little associated plasma leakage. Cycloheximide (10 mu g/site) did not significantly inhibit the neutrophil accumulation i nduced by LPS (0.1 mu g/site). In the LSR, priming i.d. injections of LPS caused a dose-dependent increase in haemorrhage and plasma leakage at skin sites after challenge with LPS (two injections of 100 mu g, i .v.). Go-injection of a single dose of cycloheximide (10 mu g/site) wi th LPS (30 mu g/site) caused a marked reduction in the amount of haemo rrhage. Local cycloheximide (10 mu g/site) administered immediately be fore LSR challenge did not affect the responses produced in the LSR.5 Neutrophil accumulation induced by TNF (0.17 mu g/site) was abolished by co-administration of p55-sf2 (3 mu g/site) whereas neutrophil accum ulation induced by i.d. LPS and produced in the RPA reaction was not a ffected. In the LSR, haemorrhage and oedema formation were inhibited b y p55-sf2 (3 mu g/site) when it was administered i.d. with the LPS pri ming injection, but not when given i.d. immediately before LSR challen ge. 6 These data suggest that the acute neutrophil accumulation produc ed in the RPA reaction and in response to i.d. LPS may not be dependen t on local protein synthesis or TNF production. On the other hand, hae morrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importan tly, haemorrhage and plasma leakage appear to be dependent on local TN F generation during the priming phase but not during the challenge sta ge of the LSR. Thus TNF appears to play a key role in the LSR in rabbi t skin.