Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF.. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 89: 4845-4849

Laboratory of Surgical Metabolism, New York Hospital-Cornell University Medical Center, NY 10021.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/1992; 89(11):4845-9. DOI: 10.1073/pnas.89.11.4845
Source: PubMed


Tumor necrosis factor alpha (TNF alpha), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNF alpha-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNF alpha, we show that sTNFR-I-TNF alpha complexes may circulate even in the absence of detectable free TNF alpha. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNF alpha are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNF alpha levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNF alpha production observed in lethal sepsis.

Download full-text


Available from: Cosmo Rock, Apr 19, 2015
  • Source
    • "This adds further to two previous studies correlating increased baseline levels of circulating sTNFRII with the development of early AMD (Klein et al. 2014) and a tendency to progression to late AMD (Seddon et al. 2005). sTNFRII is a soluble receptor for TNFa, and the plasma level of sTN- FRII has been shown to increase in response to increased levels of TNFa (Van Zee et al. 1992; Aukrust et al. 1994; Van Hauwermeiren et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: We have recently identified homeostatic alterations in the circulating T cells of patients with age-related macular degeneration (AMD). In cultures of retinal pigment epithelial cells, we have demonstrated that T-cell-derived cytokines induced the upregulation of complement, chemokines and other proteins implicated in AMD pathogenesis. The purpose of this study was to test whether increased plasma levels of cytokines were present in patients with AMD. METHODS: We conducted a case-control study. Age-related macular degeneration status was assessed using standardized multimodal imaging techniques. Plasma was isolated from freshly drawn peripheral venous blood samples and analysed for interleukin (IL)15, IL18, interferon (IFN)γ, soluble tumour necrosis factor (TNF) receptor II (sTNFRII) and complement factor H (CFH) Y402H genotype. RESULTS: We included 136 individuals with early or late forms of AMD and 74 controls. Significantly increased levels of sTNFRII were observed in patients with early or exudative AMD (p < 0.01). After adjusting for CFH Y402H genotype, age, sex and smoking history, the level of sTNFRII remained a significant predictor for prevalence of AMD with odds ratios at 3.0 in the middle and 3.6 in the highest tertiles. Levels of IL15, IL18 and IFNγ were low and not associated with AMD. CONCLUSIONS: Increased plasma level of sTNFRII is found to be associated with AMD. The data supports the observations of low-grade, systemic inflammatory alterations in patients with AMD. However, it remains to be determined whether increased levels of TNFα can be found, which directly reflects an increased activity of macrophages and T cells.
    Full-text · Article · Nov 2014 · Acta ophthalmologica
  • Source
    • "Including the level of soluble receptors with the early TNF-a response provided a more dynamic assessment of this early proinflammatory cytokine in mediating aspiration-induced ALI. TNFsRI in particular has been shown to play a crucial role in alveolar epithelial dysfunction after acid aspiration, while also blocking and attenuating the biologic effects of excessive TNF-a [43] [44]. This may help explain our observation of TNF-a levels at 5 h after low pH gastric aspiration, owing to a more pronounced cytoprotective response by TNFsRI in the high AGE-fed mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastric aspiration is a significant cause of acute lung injury and acute respiratory distress syndrome. Environmental risk factors, such as a diet high in proinflammatory advanced glycation end-products (AGEs), may render some patients more susceptible to lung injury after aspiration. We hypothesized that high dietary AGEs increase its pulmonary receptor, RAGE, producing an amplified pulmonary inflammatory response in the presence of high mobility group box 1 (HMGB1), a RAGE ligand and an endogenous signal of epithelial cell injury after aspiration. CD-1 mice were fed either a low AGE or high AGE diet for 4 wk. After aspiration injury with acidified small gastric particles, bronchoalveolar lavage and whole-lung tissue samples were collected at 5 min, 1 h, 5 h, and 24 h after injury. RAGE, soluble RAGE (sRAGE), HMGB1, cytokine and chemokine concentrations, albumin levels, neutrophil influx, and lung myeloperoxidase activity were measured. We observed that high AGE-fed mice exhibited greater pulmonary RAGE levels before aspiration and increased bronchoalveolar lavage sRAGE levels after aspiration compared with low AGE-fed mice. Lavage HMGB1 levels rose immediately after aspiration, peaking at 1 h, and strongly correlated with sRAGE levels in both dietary groups. High AGE-fed mice demonstrated higher cytokine and chemokine levels with increased pulmonary myeloperoxidase activity over 24 h versus low AGE-fed mice. This study indicates that high dietary AGEs can increase pulmonary RAGE, augmenting the inflammatory response to aspiration in the presence of endogenous damage signals such as HMGB1.
    Full-text · Article · Apr 2014 · Journal of Surgical Research
  • Source
    • "Both receptors are also present in soluble form and retain their affinity for TNF-. Soluble receptors competing with cell surface receptors for binding to free TNF-, because it is inactivated when bound or soluble binds receptor, the generation of these receptors actually represents an anti-inflammatory response mechanism [8]. Numerous studies have demonstrated the presence of high levels of TNF- in clinical sepsis and septic shock [9]. "

    Full-text · Article · Jan 2014
Show more