Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells

doi:10.1016/1043-4666(91)90483-T

Cytokine

Volume 3, Issue 6, November 1991, Pages 568-575

https://doi.org/10.1016/1043-4666(91)90483-T Get rights and content

Abstract

Taurolidine (Geistlich Pharm, AG, Wolhusen, Switzerland), a derivative of the amino acid taurine, is commonly used in some parts of the world as an adjunctive therapy for various infections. Its mechanism of action is thought to be related to its antimicrobial properties, including its ability to interfere with some of the biological activities of endotoxin (lipopolysaccharide, LPS). For example, taurolidine has been shown to protect animals against endotoxic shock and death. In this study we examined the ability of taurolidine to block LPS-induced tumor necrosis factor (TNF) and interleukin 1 (IL-1) synthesis in human peripheral blood mononuclear cells (PBMC) from 27 donors. We observed a dose-dependent reduction in the synthesis of these two cytokines when taurolidine was preincubated with LPS before being added to PBMC. This reduction was independent of the molar ratio of taurolidine to LPS but was related to the concentration of taurolidine present in the PBMC cultures. There was a 80 to 90% reduction in total IL-1 and TNF synthesis induced by LPS at concentrations of taurolidine of 40 to 100 μg/mL; the vehicle was without effect. Following a 30-min preincubation with PBMC, taurolidine could be washed from the cells and still suppress cytokine synthesis induced by LPS. Using release of lactic acid dehydrogenase, 100 μg/mL of taurolidine was not toxic for PBMC. Taurolidine also reduced IL-1 and TNF synthesis induced by the Staphylococcus aureus—derived toxic shock syndrome toxin-1 as well as that induced by nontoxic heat-killed Staphylococcus epidermidis organisms. These results show that taurolidine blocks the production of IL-1 and TNF in human PBMC; furthermore, they suggest that the protective effect of taurolidine may, in part, be due to its ability to reduce IL-1 and TNF synthesis during infection.

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Taurolidine improved protection against highly pathogenetic avian influenza H5N1 virus lethal-infection in mouse model by regulating the NF-κB signaling pathway
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In the peritoneum, it prevents the local recurrence and metastasis to distant organs of tumor cells by restricting the release of cytokines from macrophages (Braumann et al., 2009). Additionally, TRD inhibits the synthesis of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in mononuclear cells from human peripheral blood (Bedrosian et al., 1991). TRD induces apoptosis by activating mitochondrial cytochrome-c-dependent mechanisms and an external direct pathway in tumor cells (Neary et al., 2014).
Taurolidine (TRD), a derivative of taurine, has anti-bacterial and anti-tumor effects by chemically reacting with cell-walls, endotoxins and exotoxins to inhibit the adhesion of microorganisms. However, its application in antiviral therapy is seldom reported. Here, we reported that TRD significantly inhibited the replication of influenza virus H5N1 in MDCK cells with the half-maximal inhibitory concentration (EC₅₀) of 34.45 μg/mL. Furthermore, the drug inhibited the amplification of the cytokine storm effect and improved the survival rate of mice lethal challenged with H5N1 (protection rate was 86%). Moreover, TRD attenuated virus-induced lung damage and reduced virus titers in mice lungs. Administration of TRD reduced the number of neutrophils and increased the number of lymphocytes in the blood of H5N1 virus-infected mice. Importantly, the drug regulated the NF-κB signaling pathway by inhibiting the separation of NF-κB and IκBa, thereby reducing the expression of inflammatory factors. In conclusion, our findings suggested that TRD could act as a potential anti-influenza drug candidate in further clinical studies.
Innate immune responses to Stenotrophomonas maltophilia in immunocompromised pediatric patients and the effect of taurolidine
2013, Journal of Microbiology, Immunology and Infection
Citation Excerpt :
Its mechanism of action is presumably mediated by methylol derivatives that irreversibly destroy bacterial cell walls7 or hamper biofilm production.8 In addition, taurolidine may have an immunomodulatory potential including antiinflammatory properties in lipopolysaccharide-stimulated monocytes and inhibitory effects on bacterial adherence to epithelial cells.9–11 In this study, we evaluated the immunomodulatory role of taurolidine in our in vitro S. maltophilia sepsis model.
Stenotrophomonas maltophilia is an emerging pathogen causing invasive infections in immunocompromised pediatric patients, including neonates and pediatric oncology patients. Information on innate immune responses to S. maltophilia and its potential modulation are scarce.
We established an in vitro S. maltophilia whole blood sepsis model and studied the proinflammatory cytokine production of CD14-positive cells by flow cytometry. We compared the cytokine expression of term newborns (n = 13) and healthy adults (n = 10) and investigated in vitro responses of pediatric oncology patients after recovery from neutropenia (n = 10) with healthy adults (n = 10). We further evaluated the immunomodulatory role of the amino-acid derivative taurolidine in our in vitro sepsis model.
Proinflammatory cytokine responses to S. maltophilia were largely diminished in the neonatal population. No remarkable differences were noted for cytokine responses between pediatric oncology patients and healthy controls. Taurolidine inhibited immunoglobulin (IL)-6, IL-8 and tumor necrosis factor-alpha expression in a dose dependent-fashion in both, pediatric oncology patients and healthy controls.
Deficient immune responses to S. maltophilia require optimized prevention strategies against infection in immunocompromised patients, including neonates. Taurolidine may be an effective immunomodulatory agent in a clinical setting.
The potential protective effects of taurine on coronary heart disease
2010, Atherosclerosis
Citation Excerpt :
The production of tumor necrosis factor-α (TNF-α), an important pro-inflammatory cytokine, has been shown to be downregulated by taurolidine, a derivative of taurine. Taurolidine blocked the production of TNF-α by 50–90% in human peripheral blood mononuclear cells from healthy donors stimulated by LPS and INF-γ [33]. Additionally, the amount of TNF-α released from mouse macrophage-like RAW 264.7 cells was reduced in a dose-dependent manner by TauCl given in concentrations ranging from 0.2 to 1 mmol/L [34].
In humans, taurine (2-aminoethanesulfonic acid) is mainly obtained from diet. Despite the fact that the health effects of taurine are largely unknown, taurine has become a popular supplement and ingredient in energy drinks in recent years. Evidence from mechanistic and animal studies has shown that the main biological actions of taurine include its ability to conjugate bile acids, regulate blood pressure (BP), and act as a potent antioxidant and anti-inflammatory agent. These actions suggest that high levels of taurine may be protective against coronary heart disease (CHD). However, data from epidemiologic and intervention studies in humans are limited. We review what is known about taurine's metabolism, its transportation in the body, its food sources, and evidence of its effect on cardiovascular health from in vitro, animal, and epidemiologic studies. We also discuss shortcomings of the human studies that need to be addressed in the future. The identification of taurine as a preventive factor for CHD may be of great public health importance.
Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma
2007, Lung Cancer
Citation Excerpt :
These methylol-containing moieties react with bacterial cell membrane components to prevent adhesion to epithelial cell surfaces. Furthermore, reduction of tumour necrosis-α factor (TNF-α) synthesis and inhibition of the growth promoting interleukin-1β (IL-1β) production in peripheral blood cells was demonstrated upon taurolidine treatment [5]. Induction of apoptosis by taurolidine was shown in human ovarian and prostate cancer cell lines [4,6] and also in MPM [4,6].
Taurolidine and povidone-iodine (PVP-I) are used in every day clinical practice, taurolidine as a broad spectrum antibiotic, and PVP-I as an antiseptic. The type of cell death induced in malignant pleural mesothelioma (MPM) cell lines by these agents was compared, and their ability to sensitize to chemotherapy assessed. Both taurolidine and PVP-I inhibited MPM cell growth after 7.5 min incubation, but taurolidine was more effective at later time points and was more specific towards tumour cells than PVP-I. Taurolidine induced death by caspase-dependent and independent mechanisms, whereas in contrast, PVP-I induced a necrotic phenotype that was not caspase-dependent. Interestingly, both taurolidine and PVP-I induced the production of reactive oxygen intermediates and decreased mitochondrial membrane permeability, and cell death was inhibited by the oxygen scavanger N-acetyl cysteine. Taurolidine but not PVP-I treatment resulted in p53 activation in 2/3 MPM cell lines and a decrease in the protein levels of survivin, Bcl-2 and Mcl-1. Survivin also decreased in response to PVP-I whereas Bcl-xL remained unaffected by both treatments. Targeting of Bcl-xL with siRNA sensitized MPM cells to taurolidine and taurolidine treatment sensitized MPM cells to cisplatin-induced apoptosis. In conclusion, taurolidine and PVP-I are both cytotoxic to human MPM cells at early and late time points and induce reactive oxygen intermediate production. Taurolidine induces apoptosis and necrosis, activates p53 and sensitizes cells to cisplatin, whereas PVP-I inhibits cell growth via necrosis. Both agents are promising candidates for use in local treatment within multimodality concepts for MPM.
Influence of Intraperitoneal Application of Taurolidine/Heparin on Expression of Adhesion Molecules and Colon Cancer in Rats Undergoing Laparoscopy
2007, Journal of Surgical Research
Citation Excerpt :
Although we cannot rule out other intracellular effects, it might be possible that the agents have various effects on the expression of adhesion molecules as seen in our study. Taurolidine, a product deriving from the aminosulfoacid taurin, is commonly used as a synthetic broad-spectrum antibiotic in various infections [23] because of its antimicrobial [17], anti-adherent, and immunoregulatory properties [15]. Taurolidine irreversible inactivates LPS leading to a disruption of bacterial cell adhesion leading to a prevention of infection [24].
Recent experimental studies have shown that intraperitoneal administration of taurolidine/heparin causes a reduction of local tumor growth after laparoscopy in rat models. It might be that the anti-adherent activities of these agents are responsible for this effect. In this study we investigated the adhesion molecules E-cadherin, β1-integrin, and CD44.
Following a 10,000 colon adenocarcinoma cells’ (DHD/K12/TRb) intraperitoneal application a cecum resection and a partial parietal peritoneum resection (1 × 1 cm) were performed using a three trocar technique in 30 BD IX rats. After randomization in two groups, the cecum suture line and the parietal peritoneal defect were either lavaged with 1 mL of 0.5% taurolidine/10 IU heparin or with equal amounts of 0.9% normal saline solution. Rats were sacrificed four weeks after operation and total tumor growth was determined. E-cadherin, β1-integrin, and CD44 were assessed immunohistochemically on the tumor tissue.
The expression of E-cadherin was significantly reduced to 46.7% (complete loss of staining) in the taurolidine/heparin group. Although no significant difference was detected concerning the β1-integrin and CD44 expression, a slightly reduced expression level with 26.7% of negative staining in metastases of the taurolidine/heparin group was observed. The total tumor weight (171.1 ± 181.2 mg) as well as the total number of tumor lesions was also reduced by the substances compared to the control group (283.2 ± 91.4 mg).
Taurolidine/heparin led to a significant reduction of local tumor growth. Additionally a reduction of the expression of E-cadherin was observed. However, the biological behavior of this molecule is multivariant, controversial and still unclear. Further studies should elucidate its role in the epithelial tumor genesis.
Caffeine and Taurine from Energy Drinks—A Review
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Original contributionTaurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells

Abstract

Blood

J Immunol Methods

Clin Immunol Immunopathol

Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance

Science

Interleukin 1 induces a shock-like state in rabbits

Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever

J Infect Dis

Plasma IL-1β and TNFα levels in humans following cutaneous injury

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia

J Exp Med

Interleukin-1 receptor antagonist reduces mortality from endotoxin shock

Nature

Interleukin-1 receptor blockade attenuates the host inflammatory response