We examined whether the synthesis of inter leukin-1 or tumor necrosis factor, two cytokines with po tent inflammatory activities, is influenced by dietary sup plementation with n -3 fatty acids.Nine healthy volunteers added 18 g of fish-oil concen trate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1/3 and IL-1 a) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1/3 was suppressed from 7.4±0.9 ng per milliliter at base line to 4.2±0.5 ng per milliliter after six weeks of supplementa tion (43 percent decrease; P = 0.048). Ten weeks after the end of n -3 supplementation, we observed a further decrease to 2.9±0.5 ng per milliliter (61 percent decrease;

Interleukin-6 (IL-6) shares several biologic properties with IL-1, including hematopoietin-1 activity and stimulation of T cells. Because many of their biologic activities overlap, we developed and used a specific radioimmunoassay (RIA) for IL-6 to compare production of this cytokine on a molar basis with that of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF)alpha. The RIA correlated well with the hybridoma bioassay for IL-6 (r = .87, P less than .001). Freshly isolated human peripheral blood mononuclear cells (PBMC) cultured in the absence of stimuli did not produce IL-6 in most cases. Kinetics of secretion and cell-association of IL-6 were studied. In contrast to IL-1 alpha but similar to TNF, IL-6 was almost entirely secreted into the extracellular fluid. Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6. However, on a molar basis PBMC produced approximately two to three times less IL-6 than IL-1 alpha, IL-1 beta, or TNF, regardless of the stimulus. The amount of IL-6 produced from PBMC was consistent when measured in the same subjects six time during a 12-week period. In a cohort of 38 donors, the coefficient of variation for IL-6 production was .32, compared with .92 for IL-1 beta and .96 for TNF. Comparing cytokine production by PBMC, there was a significant correlation between IL-6 and IL-1 beta (r = .72) and between IL-6 and TNF (r = .66). IL-6 did not stimulate IL-1 beta or TNF production, but suppressed IL-1 beta and TNF production induced by LPS or PHA by 30% (P less than .01). This suppression of IL-1 beta and TNF by IL-6 appears to be on the level of transcription.

We studied the in vitro production of interleukin-2 in nine healthy volunteers who added 18 g/day of fish-oil concentrate rich in n-3 polyunsaturated fatty acids to their normal Western diet for a period of 6 weeks. Interleukin-2 synthesis from stimulated peripheral blood mononuclear cells was suppressed from 6.2 ng/ml at baseline to 2.2 ng/ml 10 weeks after the end of n-3 fatty acid supplementation (65% decrease; P = .04). At the same time phytohemagglutinin-induced proliferation of mononuclear cells was suppressed by 70% from the presupplement level. Interleukin-2 production returned to the premedication level at the end of the studies. The results suggest that the effect of dietary n-3 fatty acids in some diseases may be mediated in part by decreased production of interleukin-2 and decreased mononuclear cell proliferation.

Interleukin-6 (IL-6) shares several biologic properties with IL-1, including hematopoietin-1 activity and stimulation of T cells. Because many of their biologic activities overlap, we developed and used a specific radioimmunoassay (RIA) for IL-6 to compare production of this cytokine on a molar basis with that of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF)alpha. The RIA correlated well with the hybridoma bioassay for IL-6 (r = .87, P less than .001). Freshly isolated human peripheral blood mononuclear cells (PBMC) cultured in the absence of stimuli did not produce IL-6 in most cases. Kinetics of secretion and cell-association of IL-6 were studied. In contrast to IL-1 alpha but similar to TNF, IL-6 was almost entirely secreted into the extracellular fluid. Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6. However, on a molar basis PBMC produced approximately two to three times less IL-6 than IL-1 alpha, IL-1 beta, or TNF, regardless of the stimulus. The amount of IL-6 produced from PBMC was consistent when measured in the same subjects six time during a 12-week period. In a cohort of 38 donors, the coefficient of variation for IL-6 production was .32, compared with .92 for IL-1 beta and .96 for TNF. Comparing cytokine production by PBMC, there was a significant correlation between IL-6 and IL-1 beta (r = .72) and between IL-6 and TNF (r = .66). IL-6 did not stimulate IL-1 beta or TNF production, but suppressed IL-1 beta and TNF production induced by LPS or PHA by 30% (P less than .01). This suppression of IL-1 beta and TNF by IL-6 appears to be on the level of transcription.

No abstract

Numerous studies have reported altered in vitro cytokine production in various diseases. In the present study we used specific immunoassays to quantitate production of interleukin 1 beta (IL 1 beta), IL 1 alpha, tumor necrosis factor (TNF) and IL 2 from human peripheral blood mononuclear cells (PBMC). The distribution of cell-associated and secreted cytokines was studied in PBMC of 21 individuals; in response to lipopolysaccharide (LPS) the proportion of cell-associated IL 1 beta ranged from 13% to 56%, for IL 1 alpha 29% to 98%, and for TNF 2% to 17%. In a larger cohort of 32 subjects, the total amount of immunoreactive cytokines produced in response to LPS or phytohemagglutinin was normally distributed within the study group. Mean production of IL 1 alpha in response to LPS was 10.1 ng/ml and exceeded production of IL 1 beta (5.6 ng/ml) and TNF (2.2 ng/ml). The distribution pattern was characterized by high intersubject variability extending over two orders of magnitude and the presence of high and low "producers". Production of IL 1 alpha and IL 1 beta correlated (R = 0.69). In contrast, production of IL 1 beta did not correlate with production of TNF or IL 2. Indomethacin present during stimulation of PBMC increased the amount of IL 1 beta produced and showed a high correlation (R = 0.83) compared to cultures without indomethacin. Thus, low production of IL 1 beta in certain subjects appears not to be due to inhibitable levels of cyclooxygenase products. In a retrospective study, PBMC from 12 subjects who had taken oral cyclooxygenase inhibitors during the preceding 7 days produced 43% more IL 1 beta than subjects who did not take these drugs (p less than 0.05). These studies demonstrate that the amount of cytokine synthesized by PBMC (a) is regulated independently for IL 1, TNF and IL 2; (b) correlates for IL 1 beta and IL 1 alpha; (c) is intrinsic for low and high "producers", and (d) production of IL 1 beta increases with the use of oral cyclooxygenase inhibitors.

SUMMARYWe investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1a (IL1a), IL-1b, IL-2, IL-6, tumour necrosis factor-a (TNF) and granulocyte-macrophage colonystimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1b and TNF synthesis induced by exogenous IL-1a was elevated threefold compared to the pre-aspirin value (P 0 . 01 and P 0 . 005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E 2 (PGE 2 ). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS-or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1a-induced synthesis of IL-1b was elevated to a mean individual increase of 538% (P < 0 . 001) and synthesis of TNF was elevated to 270% (P < 0 . 001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE 2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE 2 -mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.

Background: Hemodialysis-induced hypotension is one of the most common problems in patients, who undergo hemodialysis. Evidence suggests the positive impacts of Selective Serotonin Reuptake Inhibitors (SSRIs) on preventing hypotension during dialysis. The current study investigated the hypothesis that sertraline could effectively prevent hypotension during hemodialysis. Methods: In a clinical trial, 30 patients on hemodialysis with hypotension during hemodialysis, who were referred to Tabriz University of Medical Sciences were enrolled. Patients were treated with sertraline at a dose of 50 mg daily for 2 weeks. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate of patients before and after the intervention were measured and compared. Adverse events due to the administration of sertraline were also evaluated in the patients. Results: Of the 30 studied patients, 17 (56.7%) were male and 13 (43.3%) were female. Systolic blood pressure, diastolic blood pressure, and mean arterial pressure increased significantly after sertraline administration (P = 0.001). Also, the mean heart rate of patients significantly decreased (P = 0.001). However, headache was seen in 7 (23.3%), dizziness in 3 (10.0%), and gastrointestinal complications in 2 (6.7%) patients. Conclusions: Based on the results of this study, sertraline effectively and safely prevents hypotension during dialysis without causing serious side effects.