A CRITICAL ROLE OF THE P75 TUMOR-NECROSIS-FACTOR RECEPTOR (P75TNF-R) IN ORGAN INFLAMMATION INDEPENDENT OF TNF, LYMPHOTOXIN-ALPHA, OR THE P55TNF-R

Despite overwhelming evidence that enhanced production of the p75 tumo r necrosis factor receptor (p75TNF-R) accompanies development of speci fic human inflammatory pathologies such as multi-organ failure during sepsis, inflammatory liver disease, pancreatitis, respiratory distress syndrome, or AIDS, the function of this receptor remains poorly defin ed in vivo. We show here that at levels relevant to human disease, pro duction of the human p75TNF-R in transgenic mice results in a severe i nflammatory syndrome involving mainly the pancreas, liver, kidney, and lung, and characterized by constitutively increased NF-kappa B activi ty in the peripheral blood mononuclear cell compartment. This process is shown to evolve independently of the presence of TNF, lymphotoxin a lpha, or the p55TNF-R, although coexpression of a human TNF transgene accelerated pathology. These results establish an independent role for enhanced p75TNF-R production in the pathogenesis of inflammatory dise ase and implicate the direct involvement of this receptor in a wide ra nge of human inflammatory pathologies.