TUMOR-NECROSIS-FACTOR (TNF)-INDUCED CUTANEOUS NECROSIS IS MEDIATED BYTNF RECEPTOR-1

Tumor necrosis factor (TNF) is a central mediator of immune and inflam matory responses. Its activities have been shown to be mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75). The cytoplasmic doma ins of both TNF receptors are unrelated, suggesting that they link to different intracellular signaling pathways. To determine their role in vivo in lipopolysaccharide (LPS)- and TNF-induced skin inflammatory n ecrosis, TNFR1-, TNFR2-, TNFR1/TNFR2-, and TNF lymphotoxin-alpha (LT a lpha)-deficient mice were used. Skin abscesses were experimentally ind uced with local application of TNF or LPS. Large microscopic ulceratio ns were observed in TNF-injected wild-type animals and to a slightly l esser extent in TNFR2-deficient mice with tissue destruction in both c ases extending deep into the dermis. Tissue destruction was accompanie d by an intense immune infiltrate composed mainly of neutrophils, lymp hocytes, and macrophages. TNFR1-deficient and TNFR1/TNFR2-double-defic ient mice, however, did not exhibit any ulceration and showed only a v ery mild inflammatory infiltrate. In TNF/LT alpha-double ligand-defici ent animals, a moderate epidermal necrosis was observed with a reduced inflammatory infiltrate compared to wild-type animals. As with TNF in jections, subcutaneous injection of LPS induced a comparable pattern o f skin necrosis in wild-type and TNF receptor mutant mice, yet a sligh tly more acute inflammatory level was observed regardless of the type of animal tested. As found for TNF-induced skin necrosis, the extent o f LPS-induced skin necrosis was reduced in TNF/LT alpha-deficient mice compared to wild-type animals. The present data strongly suggest that TNFR1, rather than TNFR2, is engaged in LPS- and TNF-induced skin nec rosis and highlight the predominant role played by TNF in LPS-induced inflammatory diseases. (C) 1997 Wiley-Liss, Inc.