Acute phase proteins as protective factors against the toxicity of tumor necrosis factor.
Tumor Necrosis Factor is an endogenous messenger molecule (cytokine) exhibiting a broad range of biological activities. Of special interest is its cytotoxic activity, specific for transformed tumor cells and which results in outspoken tumor regression in experimental animals. Administration of high dose of TNF, necessary to treat internal tumors, however is currently impossible because of the pro-inflammatory properties of TNF. Injection of TNF causes significant decrease in blood pressure and serious liver-toxicity. However, the liver is not only a target organ for TNF, it also produces protecting factors. Based on our studies of the role of Interleukin-1 and Interleukin-6, two other cytokines, we investigated the protective role of a set of liver-derived proteins, the acute phase proteins. We identified two such proteins as protective factors in our mouse models: alpha-1-Acid Glycoprotein (AGP) and alpha-1-Antitrypsin (AT). Both proteins confer complete protection against TNF-induced lethality in mouse models, and are currently evaluated as adjuvans in TNF-based antitumor therapy. The protection by both proteins also brought us new insights in the mechanism of TNF-induced liver-toxicity. In this sense, molecules like elastase and Platelet Activating Factor were recognized as mediating factors.
Libert
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Laboratory of Molecular Biology, Gent University.
D000209:Acute-Phase Proteins / Q000494:pharmacology*; D000818:Animals; D005688:Galactosamine / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D009961:Orosomucoid / Q000494:pharmacology; D014176:Protein Biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000627:therapeutic use / Q000633:toxicity*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D000209:Acute-Phase Proteins; D009961:Orosomucoid; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D005688:Galactosamine