Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors.

Abstract

SummaryThe receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding spedfically 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 foUows 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.T NF, a polypeptide cytokine, produced primarily by mononuclear phagocytes, plays a key role in the initiation of the inflammatory response. It has a variety of effects, of different, even contrasting nature (1, 2). Evidence that some of these effects can be detrimental to the host have attracted attention to the mechanisms that regulate TNF function. The intracellular signals for the response to TNF are provided by cell surface receptors, of two distinct molecular species, to which TNF binds at high affinity (3, 4). Both receptors for TNF exist also in soluble forms (5-8), apparently derived by proteolytic cleavage from the cell surface forms (9). These soluble TNF receptors (sTNF-Rs) 1 can compete for TNF with the cell surface receptors and thus block its activity (5-8). It was therefore suggested that they function as physiological attenuators of the activity of TNF, safeguarding against its potentially harmful effects. We report here that the sTNF-Rs affect TNF function also by stabilizing its activity, most likely by preventing dissociation of the homotrimeric TNF molecules (10-13) to inactive monomers. Materials and Methods TNF and Its Soluble Receptors.Recombinant human TNF-c~ (TNF; 6 x 107 U/mg of protein), produced by Genentech Co.1 Abbreviations used in this paper: B-CLL, B-chronic lymphocytic leukemia; sTNF-R, soluble tumor necrosis factor receptor.(San Francisco, CA), was kindly provided by Dr. G. Adolf, of the Boehringer Institute (Vienna, Austria). Radiolabeling of the TNF with mI was performed by the chloramine-T method, as previously described (14). Native TNF was produced by stimulation of human peripheral mononuclear phagocytes with bacterial lipopolysaccharide for 6 h, as described elsewhere (15), and used without further purification. The soluble forms of the type I (p55) and type II (p75) TNF receptors (sTNF-RI and sTNF-RII, previously called TBPI and TBPII [81) were isolated from normal urine by ligand (TNF) affinity purification followed by reversed-phase HPLC, as described before (8).Cells. ...

Establishment of a cut‐point value of serum TNF‐α levels in the metabolic syndrome

“…Therefore, our data clearly justify further analysis of the clinical utility of TNF-a in MS with significantly larger cohorts. In addition, the concentration of TNF-a receptors should be measured because these receptors modulate TNF-a bioactivity in MS patients (24). In addition, an analysis of genetic TNF-a polymorphisms associated with higher serum TNF-a levels, and the relationship of putative polymorphisms with MS in the Mexican population, should be undertaken.…”

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

“…can no longer interact with the membrane forms and, therefore, it has been speculated that the presence of the soluble forms may constitute a way of regulating TNF actions [21].…”

TNFα blockade in human diseases: Mechanisms and future directions

“…TNF binding to the cell surface receptors is prevented [7], signal transduction is checked, and hence TNFα-induced proinflammatory activity is inhibited [6]. Of note, low concentrations of soluble TNF receptors stabilize the structure of TNFα, but higher concentrations inhibit TNFα binding to TNFRI and TNFRII on target cells [8]. ETA is administered as subcutaneous (s.c.) injections of 25 mg twice a week or 50 mg s.c. once a week.…”