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Biomedical subjects

A Waage

Publications and source records attributed to A Waage.

At least 91 records · Page 5Linked to original sources
PubMed1992

Effect of pyridoxine on tumor necrosis factor activities in vitro.

Clinical trials with tumor necrosis factor (TNF) as an antitumor agent have so far given rather disappointing results. In this study we show that the naturally occurring vitamin B6 compound, pyridoxine, enhances TNF-induced cytolysis of three subclones of a mouse fibrosarcoma cell line (WEHI 164). The degree of pyridoxine-induced enhancement of TNF cytotoxicity seems to be dependent on the cells sensitivity to TNF, as the enhancement was much more pronounced in the relatively TNF resistant subclone act-R(cl.12)-WEHI 164, than in the very TNF sensitive subclone WEHI 164 clone 13. Furthermore, our study shows that pyridoxine, in contrast to its enhancing effect on TNF-induced cytotoxicity, rather inhibits TNF-induced growth of human FS-4 fibroblasts. Pyridoxine also enhances lymphotoxin (LT)-induced tumor cell killing and inhibits LT-induced fibroblast growth. Pyridoxine is a relatively non-toxic agent in vivo. Our results suggest that a combination of TNF and pyridoxine may be more efficient than TNF alone, in the treatment of cancer patients.

Animals↗
PubMed1992

Different role of cytokine mediators in septic shock related to meningococcal disease and surgery/polytrauma.

So far, there has been a tendency towards a uniform concept of the role and kinetics of TNF and other cytokines in septic shock. However, our comparison of data from different groups of shock patients clearly demonstrates marked differences. On the one hand, the cytokine pattern in experimental septic shock and meningococcal disease has similarities which include early burst releases of TNF and IL-6. On the other hand, intensive care unit patients which includes patients with polytrauma, surgery, burns and other underlying diseases have a completely different pattern of appearance of TNF and IL-6 in the circulation. We have not been able to detect bioactive TNF in the circulation of these patients, whereas others have measured elevated levels of immunoreactive TNF. Bioactive IL-6 can be detected in serum; however, the levels are often fluctuating and there is no common pattern of appearance. These differences probably reflect differences in the release of endotoxin and the immunological status of the patients. TNF inhibitors and soluble TNF receptors probably play an important role. Experimental models for septic shock most commonly use administration of live bacteria or endotoxin to anesthesized healthy animals. This appears to be a good model for meningococcal disease, but not for intensive care unit patients.

Bacteremia↗
PubMed1992

Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice.

We administered a neutralizing monoclonal antibody to tumor necrosis factor (TNF) during infection with Candida albicans in normal and granulocytopenic mice. Mice were rendered granulocytopenic (less than 0.1 x 10(9) granulocytes per liter) with cyclophosphamide. Growth of C. albicans from the kidneys was significantly increased in normal mice treated with the antibody to TNF, compared with that in control mice, after 36 h (3.6 x 10(4) +/- 1.2 x 10(4) CFU per kidney versus 9.1 x 10(3) +/- 6.2 x 10(3) CFU per kidney; P less than 0.05) and after 72 h (3.7 x 10(6) +/- 2.7 x 10(6) CFU per kidney versus 2.3 x 10(4) +/- 1.3 x 10(4) CFU per kidney; P less than 0.01). In granulocytopenic mice, the antibody to TNF had no effect on the growth of C. albicans from the kidneys. Furthermore, our study showed that the cytokines TNF and interleukin-6 (IL-6) were produced in a dose-dependent manner during C. albicans infection. TNF was detectable between 6 and 60 h, with peak levels at 24 h. Both TNF and IL-6 levels were significantly higher in cyclophosphamide-treated mice than in normal mice. Heat-inactivated C. albicans induced a TNF response different from that induced by viable C. albicans, with an early peak occurring at 3 to 4 h and declining to non-detectable levels after 15 to 24 h. Peak levels of TNF obtained with heat-inactivated C. albicans were lower than those obtained with viable C. albicans. Our study demonstrates that TNF and IL-6 are produced systemically during C. albicans infection and suggests that TNF is essential for granulocyte antifungal activity in vivo.

Agranulocytosis↗
PubMed1992

Magnesium deficiency diagnosed by an intravenous loading test.

Magnesium deficiency is common but difficult to diagnose and to assess in clinical practice. The use of a magnesium loading test was therefore evaluated to diagnose magnesium deficiency in 661 hospitalized patients with medical conditions assumed to interfere with magnesium uptake and excretion. Thirty millimoles of magnesium sulphate were administered intravenously during 8 h as a loading test and related to the urinary excretion in the following 24 h. A group of 30 patients without any known predisposition for magnesium deficiency and a group of 27 healthy volunteers served as controls. The mean (with 95% confidence interval) magnesium retention was 4 (-2-10)% in the control group of patients and 3 (-2-8)% in healthy subjects. A significantly higher retention was observed in all the groups of the patients: atrial fibrillation 18 (11-25)%, other arrhythmias 18 (11-24)%, hypertension 27 (20-33)%, coronary artery disease 25 (20-30)%, congestive heart failure 31 (26-37)%, cerebrovascular events 38 (24-51)%, gastrointestinal disorders 22 (14-29)%, diabetes mellitus 16 (9-22)%, and alcoholics 33 (29-36)%. The percentage of patients with a retention greater than mean + 2 SD of the two control groups varied between 22% and 54% among the different patient groups. The mean serum magnesium among the patient groups was similar to the control group of patients, except for the alcoholics, hypertensives and young healthy controls, who had significantly reduced levels. Magnesium retention was significantly correlated to age and renal function, and among the alcoholics negatively correlated to serum magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Development of immunoassays for the detection of soluble tumour necrosis factor receptors.

Immunoassays were established for the detection of the 55 kDa and 75 kDa tumour necrosis factor receptor (TNFR) fragments present in urine. The immunoassays were based on pairs of monoclonal TNFR antibodies directed against different epitopes of the 55 kDa and 75 kDa TNFRs. The immunoassays were judged to be specific for unoccupied TNFR since the signals were inhibited by adding recombinant human or murine TNF-alpha, and to a lesser extent by rTNF-beta (LT). Other cytokines such as IL-1 beta, IL-2 or rIFN-gamma did not affect the signal. In a preliminary screening it was found that urines from febrile patients contained higher amounts of 55 kDa and 75 kDa TNFR fragments than did urine from non-febrile individuals. The immunoassays could be used to monitor the purification of the two types of TNFR from the same febrile urine. Furthermore, the sensitivity and the speed of the assay could be increased by the use of magnetic beads as a solid support in the assay.

Fever↗
PubMed1991

Cytokine-associated tissue injury and lethality in mice: a comparative study.

A comparative study was performed to examine the lethal effects of several cytokines injected into mice sensitized with actinomycin D (Act-D). Consistent with published data, human tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) (0.2-5 micrograms) caused the death of the animals within 8-12 hr after injection. Human interleukin-6 (IL-6) and interleukin-8 (IL-8) (0.6-6 micrograms) known to be induced by TNF-alpha did not show any lethal effects, indicating that TNF-alpha-associated lethality is not mediated by IL-6 or IL-8. Human tumor necrosis factor-beta (TNF-beta) (also called lymphotoxin), which shares structural and functional properties with TNF-alpha, was as potent as TNF-alpha in its lethal effects. Murine interferon-gamma (IFN-gamma) (0.04-5 micrograms) was also tested and showed no lethal effects in this model. In addition, a synthetic peptide corresponding to amino acid residues 163-171 of IL-1 beta, and which has been shown to lack the inflammatory effects of IL-1 beta, also caused no lethality among Act-D sensitized mice. The pretreatment of mice with IL-6, IL-8, or IFN-gamma had no protective effects on TNF-alpha or IL-1 beta-induced lethality in contrast to the protection observed by a pretreatment with TNF-alpha/IL-1 beta themselves or with endotoxin. Histopathologic data showed that severe tissue injury in vital organs is associated with the rapid lethality among sensitized mice.

Animals↗
PubMed1991

Current understanding of the pathogenesis of gram-negative shock.

There is increasing evidence that gram-negative bacteria via endotoxin induce the excessive production of inflammatory cytokines, which are active in the pathogenesis of septic shock, multiorgan failure, and ARDS. In animals the injection of TNF induces pathophysiologic and histopathologic changes that are characteristic of the septic shock syndrome, and in patients there is a close association between levels of TNF and the severity of the shock. IL-1 and IFN-gamma markedly potentiate the toxic TNF effects in animal experiments. IL-6 is frequently released into serum during septic shock, and its levels are associated with the severity of the shock. The cytokine is probably not directly involved in the pathogenesis of the shock but may contribute to fever, neutrophilia, and production of acute-phase proteins. Endothelial cells and neutrophils are important target cells for the cytokines in mediation of septic shock and late complications. Underlying conditions like cancer, trauma, burns, and other kinds of stress may alter the induction mechanism of the cytokines and the susceptibility of the organism. The pathogenetic significance of TNF and other cytokines in different categories of septic shock remains to be clarified.

Animals↗
PubMed1990

Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts.

We have examined the effect of dexamethasone (DM) and cortisol on the production of interleukin (IL)6 from the murine macrophage cell line RAW264.9, human monocytes, human endothelial cells and the human fibroblast cell line FS4. In RAW264.9 cells DM in the concentration range 10(-9) M to 10(-6) M inhibited the lipopolysaccharide (LPS)-induced production of IL6 by 10% to 90%. Cortisol had a similar effect, but was about 25 times less potent than DM. Also, when 10(-6) M of DM was added to the cultures after addition of LPS, it completely inhibited the residual 24-h production of IL6. Corresponding to the effect on IL6 production, DM (10(-6) M) reduced the mRNA levels for IL6 in the RAW264.9 cells. The glucocorticoid analogue RU 486 competes with DM and cortisol for the glucocorticoid receptor and reversed the inhibitory effect of DM, demonstrating that DM exerts its effect via the glucocorticoid receptor. DM also had an inhibitory effect on LPS-stimulated IL6 production in freshly isolated human monocytes, and on IL 1-stimulated IL6 production in human endothelial cells and FS4 fibroblasts. These results demonstrate that DM via a receptor-mediated mechanism inhibits IL6 production at the transcriptional level, and this may contribute to the anti-inflammatory and immunosuppressive effect of glucocorticoids.

Animals↗
PubMed1990

Regulation of interleukin-2 and interleukin-6 production from T-cells: involvement of interleukin-1 beta and transforming growth factor-beta.

The effect of recombinant (r) interleukin-1 beta (rIL-1 beta) and transforming growth factor-beta (TGF-beta) on the production of interleukin-2 (IL-2) and interleukin-6 (IL-6) from an antigen-specific (LBRM-33-1A5) and an antigen-nonspecific (EL-4-NOB-1) T-cell line was investigated. rIL-1 beta induced the production of IL-2 and IL-6 from EL-4-NOB-1 cells in a dose-related manner. The LBRM-33-1A5 cells required phytohemagglutinin (PHA) in addition to rIL-1 beta in order to produce IL-2 and IL-6. IL-2 production was found to precede IL-6 production in both cell lines. No IL-2 or IL-6 production was observed by adding r murine tumor necrosis factor-alpha or r murine interferon gamma to the cells. The presence of 1 ng/ml TGF-beta reduced IL-2 and IL-6 production from both T-cell lines by more than 80%. The inhibition of IL-2 and IL-6 production was still evident by a concentration as low as 10 pg/ml of TGF-beta. rIL-1 beta and PHA also stimulated murine thymocytes to produce IL-6 which was inhibited up to 85% in the presence of 1 ng/ml TGF-beta. Taken together these results suggest that TGF-beta may suppress immune responses by inhibiting the endogenous production of IL-2 and IL-6.

Animals↗
PubMed1989

Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response.

We examined the cerebrospinal fluid (CF) taken on admission from 60 patients with infections caused by Neisseria meningitidis for presence of TNF-alpha, IL-1, and IL-6. TNF-alpha was detected in CF in 55 and 19% (p = 0.03), IL-1 in 50 and 15% (p = 0.05), and IL-6 in 98 and 100% of patients with meningitis and septic shock/bacteremia, respectively. The median IL-6 concentration in CF in patients with meningitis was 154 ng/ml, and in patients with septic shock/bacteremia it was 42 ng/ml (p = 0.001). The level of LPS in CF correlated with the level of TNF-alpha (r = 0.91, p less than 0.001), but not with the level of IL-1 and IL-6. CF levels of TNF-alpha, IL-1, and IL-6 correlated with each other (r = 0.34-0.54, p less than 0.01), with the protein concentration (r = 0.34-0.62, p less than 0.01) and inversely with the CF/blood glucose ratio (r = -0.34 to -0.67, p less than 0.01). Only the Il-6 level correlated with the leukocyte count (r = 0.37, p less than 0.01). In rabbits TNF-alpha, IL-1, and IL-6 activities sequentially appeared in CF within 3 h of injection of meningococcal LPS or viable meningococci, whereas the main infiltration of granulocytes started after 4 h. TNF-alpha was detected in serum at concentrations less than 1/100 of those in CF after administration of LPS into the subarachnoid space, and conversely, TNF-alpha was detected in CF at concentrations 1/100 of those in serum after intravenous injection of LPS. The results demonstrate that TNF-alpha, IL-1, and IL-6 are sequentially produced in the initial phase of the local inflammatory response caused by meningococci, and that the subarachnoid space and systemic circulation are separate compartments with respect to production of TNF-alpha, IL-1, and IL-6.

Adolescent↗
PubMed1989

The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome.

Serum samples from patients with meningococcal disease were examined for the presence of IL-6, TNF-alpha, and LPS. Median serum concentration of IL-6 was 1,000 times higher in patients with septic shock (189 ng/ml) than in patients with bacteriaemia, meningitis, or combined septic shock and meningitis. 11 of 21 patients with serum levels greater than 3.0 ng/ml died, whereas all 58 patients with serum levels at less than or equal to 3.0 ng/ml, survived. All four patients with serum IL-6 levels greater than 750 ng/ml, died. IL-1 was detected in serum from three patients who also had high serum levels of IL-6, TNF-alpha, and LPS, and rapidly fatal courses. IL-6 appeared to be released into serum later than TNF-alpha, and was detected in serum for up to 36 h. The half-life of IL-6 and TNF-alpha was calculated to be 103 +/- 27 min and 70 +/- 11 min, respectively. These data indicate that a complex pattern of cytokines exists in serum from patients with meningococcal septic shock, and that the release of IL-6 and IL-1, in addition to TNF-alpha, is associated with fatal outcome.

Humans↗
PubMed1989

Cytokine regulation of interleukin 6 production by human endothelial cells.

The influence of recombinant (r) human tumor necrosis factor alpha (rTNF-alpha), r human interleukin 1 beta (rIL-1 beta), and r human interferon gamma (rIFN-gamma) on the production of interleukin 6 (IL-6) by human endothelial cells (HEC) was investigated. The addition of 1-100 U/ml of either rTNF-alpha or rIL-1 beta to cultures of HEC monolayers caused a dose-related increase in IL-6 production as detected after 24 hr of incubation. In contrast to rIL-1 beta and rTNF-alpha, the use of up to 1000 U/ml of rIFN-gamma caused only a moderate increase in IL-6 production. However, significantly greater quantities of IL-6 were produced by HEC monolayers subjected to 1000 U/ml of rIFN-gamma in combination with 1-100 U/ml of rTNF-alpha. Furthermore, the addition of graded concentrations of human transforming growth factor beta (TGF-beta) to cultures resulted in a dose-related inhibition of rIL-1 beta- and rTNF-alpha-induced IL-6 production by HEC. The results demonstrate that rIL-1 beta and rTNF-alpha share the ability to stimulate HEC for production of IL-6 and indicate that TGF-beta may act as an immunosuppressive agent, at least partially, through its ability to inhibit the action of TNF-alpha and IL-1 on endothelial cells.

Biological Factors↗
PubMed1989

Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo.

The ability of Escherichia coli-derived lipopolysaccharide (LPS), recombinant (r) interleukin 1-beta (rIL-1 beta), and r murine tumor necrosis factor-alpha (rMuTNF-alpha) to induce interleukin 6 (IL-6) production in vivo was investigated. Peak serum IL-6 concentration was attained after 2 hr of LPS injection into mice. The coinjection of antiserum against rMuTNF-alpha with LPS resulted in a reduction of the induced serum IL-6 level, indicating the involvement of endogenous TNF-alpha in LPS induction of IL-6. Recombinant IL-1 beta and rMuTNF-alpha injected directly caused the production of substantial amounts of IL-6 within 30 min. The injection of a combination of rIL-1 beta and rTNF-alpha induced a significantly greater level of IL-6 than either agent alone. The greater level of serum IL-6 was associated with hypothermia and an increased lethality among mice injected with both cytokines. These data demonstrate the abilities of IL-1 beta and TNF-alpha to induce IL-6 production in vivo and indicate that LPS induction of IL-6 may be mediated, at least partially, through TNF-alpha action. The data describe a new in vivo biologic activity shared between IL-1 beta and TNF-alpha and suggest that IL-6 may be an important effector in the manifestation of TNF-alpha and IL-1 beta actions in vivo.

Animals↗
PubMed1989

Interleukin-6 in synovial fluid from patients with arthritis.

Synovial fluid and serum from patients with rheumatoid arthritis, other inflammatory arthritides, and traumatic arthritis were assayed for the presence of interleukin-6 (IL-6) by means of an IL-6-dependent mouse hybridoma cell line. The cytokine was detected in all the samples of synovial fluid (range 50-22000 U/ml). IL-6 in synovial fluid was positively correlated (r = 0.58, P = 0.03) with the erythrocyte sedimentation rate in patients with inflammatory arthritis. In serum, the concentration of IL-6 was slightly elevated in some patients with rheumatoid arthritis. The results demonstrate that IL-6 is released into synovial fluid in joints affected by arthritis, and there appears to be an association between the levels of IL-6 and disease activity.

Adolescent↗