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A Critical Role of the p75 Tumor Necrosis Factor Receptor (p75TNF-R) in Organ Inflammation Independent of TNF, Lymphotoxin , or the p55TNF-R

From the Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Hellas

Despite overwhelming evidence that enhanced production of the p75 tumor necrosis factor receptor (p75TNF-R) accompanies development of specific 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 defined in vivo. We show here that at levels relevant to human disease, production of the human p75TNF-R in transgenic mice results in a severe inflammatory syndrome involving mainly the pancreas, liver, kidney, and lung, and characterized by constitutively increased NF-B activity in the peripheral blood mononuclear cell compartment. This process is shown to evolve independently of the presence of TNF, lymphotoxin , 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 disease and implicate the direct involvement of this receptor in a wide range of human inflammatory pathologies.

Key Words: transgenic model • sepsis • ligand-independent signaling • NF-B activation

This project was supported in part by the Hellenic Secretariat for Research and Technology and European Commission Grants BIO4-CT96-0077 and BIO4-CT96-0174.

Abbreviations used: DAB, diaminobenzidine; DTT, dithiothreitol; LT, lymphotoxin .

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