Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock.

Abstract

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.

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

“…These soluble receptors can compete for TNF-a with the cell-surface receptors, thus blocking its bioavailability and activity, with the amount and speed of receptor shedding being linearly correlated with the serum TNF-a levels (Aderka et al, 1998). Similarly, no significant shedding of circulating TNF-a receptors was observed up to the dose of 0.8 mg m À2 in this study.…”

Plasma adiponectin concentration and tumor necrosis factor-α system activity in lean non-diabetic offspring of type 2 diabetic subjects

“…The role of TNF-a receptors is not entirely understood. It is proposed that sTNFRs might inactivate TNF-a or stabilize the bioactivity of the cytokine (38,39). sTNFR2 is considered as the best predictor of local TNF-a activity (40,41).…”

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

“…Activation of p55 generally results in gene activation that leads to induction of inflammatory and cytotoxic responses, while activation of TNFR2 is associated with thymocyte proliferation and T-cell activation. In response to TNF binding, lipopolysaccharide (LPS) and several other stimuli in the extracellular domains of both TNFRs are released by proteolytic cleavage and these soluble TNFR (sTNFR) forms function as inhibitors of TNF signaling (1,7,18,40). TNF has a role in several viral diseases of the central nervous system (CNS), including, for example, those caused by human immunodeficiency virus, feline immunodeficiency virus, herpes simplex virus (HSV), cytomegalovirus, Epstein-Barr virus, Sindbis virus, and Theiler's murine encephalomyelitis virus, with effects ranging from protective to toxic (31,52).…”