DIFFERENCES IN THE SHEDDING OF SOLUBLE TNF RECEPTORS BETWEEN ENDOTOXIN-SENSITIVE AND ENDOTOXIN-RESISTANT MICE IN RESPONSE TO LIPOPOLYSACCHARIDE OR LIVE BACTERIAL CHALLENGE

TNF-alpha plays a pivotal role in the pathogenesis of septic shock. It exerts its effects by binding two cell surface receptors, designated TNF-R I and II, also referred to as the p55 and p75 receptors, respect ively. TNF-Rs are transmembrane proteins, which on cleavage of their e xtracellular domains, result in the release of soluble fragments (sTNF -R). sTNF-R levels increase markedly during infection, and may serve t o modulate TNF-alpha bioactivity. The mechanisms regulating this proce ss are uncertain. To investigate this, we measured sTNF-R release in e ndotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice given LPS or live Gram-negative bacteria. In C3H/HeN mice, there was a rapid early response during the first 4 h, and a second peak at 8 h, partic ularly noticeable in the case of the p75 receptor. Prior administratio n of neutralizing Abs to TNF-alpha or IFN-gamma had no effect on recep tor shedding. Surprisingly, C3H/HeJ mice also responded to both bacter ial challenge and to LPS by shedding sTNF-R; the magnitude and duratio n of the early response was not substantially different from C3H/HeN m ice, although the second peak was absent. Peritoneal macrophages from C3H/HeN mice responded promptly (5 h) when stimulated with LPS in vitr o, and by 22 h levers had increased five- to 10-fold. In contrast, cel ls from C3H/HeJ mice demonstrated only a very modest response at 22 h following maximal stimulation. The data suggest that there may be at l east two separately regulated pathways that control sTNF-R shedding in these mice.