Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock.
Journal - The Journal of clinical investigation (UNITED STATES )
We examined the kinetics of shedding of the soluble TNF receptors (TNF-Rs) in response to TNF leakage during isolated limb perfusion procedures and correlated them to the resulting hemodynamic effects. Shedding of the TNF-Rs started 7 min after TNF leakage into the systemic circulation. Three waves of shedding were observed peaking at 1, 8-12, and 48-72 h both in vivo and in cell cultures. The soluble receptors prolonged the half-life of TNF in the systemic circulation to 2.5-6 h. Excess shedding of the p75 compared with p55 TNF-Rs was noted during the first wave. The amount and speed of shedding of the p75 TNF-Rs were proportional to the serum TNF levels (P < 0.001). A maximal shedding capacity was attained only during the first wave of shedding, at TNF concentrations of approximately 1.5 ng/ml. Above this level, the linearity between TNF and its soluble receptors was lost. TNF-induced hypotension coincided with the initial imbalance between the concentrations of TNF and its soluble receptors. Despite the spontaneous correction of this imbalance at 8-12 h, the hemodynamic and biochemical alterations persisted and were further aggravated at 18 h, suggesting that other factors induced earlier by TNF are responsible for the perpetuation of the hemodynamic instability. This study may provide the basis for a more physiological therapeutic approach to TNF neutralization in septic shock patients.
|ISSN : ||0021-9738|
|Mesh Heading : ||Adult Aged Antigens, CD Chemotherapy, Cancer, Regional Perfusion Female Hela Cells Humans Kinetics Male Middle Aged Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Recombinant Proteins Shock, Septic Solubility Time Factors Tumor Necrosis Factor-alpha administration & dosage metabolism pharmacology administration & dosage pharmacology|
|Mesh Heading Relevant : ||metabolism methods metabolism physiopathology metabolism|
The potential biological and clinical significance of the soluble tumor necrosis factor receptors.
Journal - Cytokine & growth factor reviews (ENGLAND )
The role of TNF receptors (TNF-Rs) is not limited to signal transduction but includes extracellular regulatory functions affecting systemic TNF bioavailability. This review summarizes the regulation of TNF-R shedding and its kinetics, the complex interaction between the soluble receptors and their ligand in vitro and in vivo, and the potential diagnostic, prognostic and therapeutic value of the soluble receptors in malignant, inflammatory, infectious and autoimmune disorders.
|ISSN : ||1359-6101|
|Mesh Heading : ||Animals Autoimmune Diseases Clinical Trials as Topic Communicable Diseases Humans Inflammation Mice Myocardium Neoplasms Receptors, Tumor Necrosis Factor Sepsis Solubility Tumor Necrosis Factor-alpha drug therapy drug therapy metabolism metabolism blood drug therapy metabolism|
|Mesh Heading Relevant : ||metabolism metabolism metabolism physiology metabolism|
Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors.
Journal - The Journal of experimental medicine (UNITED STATES )
The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell-associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on prolonged treatment with this cytokine are augmented, reflecting an attenuation by the sTNF-Rs of spontaneous TNF activity decay. Evidence that this stabilization of TNF activity by the sTNF-Rs follows from stabilization of TNF structure within the complexes that TNF forms with the sTNF-Rs is presented here, suggesting that the sTNF-Rs can affect TNF activity not only by interfering with its binding to cells but also by stabilizing its structure and preserving its activity, thus augmenting some of its effects.
|ISSN : ||0022-1007|
|Mesh Heading : ||Cell Count Cells, Cultured Chromatography, Gel Enzyme-Linked Immunosorbent Assay Fibroblasts Humans Kinetics Leukemia, Lymphocytic, Chronic, B-Cell Receptors, Cell Surface Receptors, Tumor Necrosis Factor Recombinant Proteins Tumor Cells, Cultured Tumor Necrosis Factor-alpha metabolism metabolism|
|Mesh Heading Relevant : ||metabolism metabolism|