Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor alpha

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) were determined in the plasma of long-term hemodialysis (HD) patients and uremic (UR) patients undergoing their first dialysis session using either cellulosic (CUP) or synthetic (PAN-AN 69) membrane-equipped dialyzers. In long-term HD patients, plasma IL-1 and TNF alpha levels were significantly increased compared to their levels in normal subjects. During a single dialysis session, a significant increase in IL-1 but not in TNF alpha was observed. In not yet dialyzed UR patients, IL-1 plasma levels did not differ from those observed in normal subjects. By contrast, TNF alpha was found significantly increased although less than in long-term HD patients. During the first dialysis session, no significant increase was observed in the levels of either monokine. Lastly, regardless of the group of patients, no significant influence of the dialysis membrane could be detected, suggesting that the observed changes are not exclusively secondary to the activation of complement. Altogether, these results suggest that the passage of the blood through the extracorporeal dialysis circuit triggers the secretion of IL-1 and further exacerbates that of TNF alpha by monocytes. The presence of increased TNF alpha in the plasma of first-dialysis UR patients suggests that factors unrelated to dialysis contribute to the activation of monocytes in these patients. Lastly, the concomitant presence of IL-1 and TNF alpha in the plasma of long-term HD patients could be responsible for some of the clinical features observed in these patients, and provides strong evidence favoring the concept that HD can be assimilated to a recurrent acute-phase inflammatory response.     

Endotoxins modulate chronically tumour necrosis factor {alpha} and interleukin 6 release by uraemic monocytes

We examined in vivo the release of tumour necrosis factor alpha(TNF) and interleukin 6 (IL-6) by uraemic monocytes upon stimulationwith endotoxin-contaminated bicarbonate concentrate. Twelveuraemic patients underwent 1-month-subsequent periods of standardhaemodialysis (SHD) with cuprophane (CU), a high-complement-activatingmembrane (6 patients), or haemodiafiltration (HDF) with polyacrylonitrile(PAN), a low-complement-activating membrane (6 patients), byusing a dialysate prepared with either non-sterile bicarbonateconcentrate tanks (phase 1) or sterile bicarbonate concentratebags (phase 2). TNF and IL-6 concentrations were determinedin monocyte supernatants by ELISA; endotoxin levels in bicarbonateconcentrates were measured by a chromogenic limulus amoebocytelysate (LAL) assay. A significant increase in LAL reactivity was found in bicarbonateconcentrate tanks compared to sterile bags (P<0.001). Non-steriledialysate caused a significant (P<0.001) predialytic increasein monocyte TNF release as compared to controls and nondialyseduraemic patients. One month treatment with sterile bicarbonatesignificantly decreased TNF predialytic activity in monocytesupernatants (P<0.001) to levels closer to those of non-dialyseduraemic patients. A similar decrease was observed for IL-6 production.Dialytic treatment induced a further increase in both TNF andIL-6 production, particularly in phase 1. When uraemic patientswere examined separately according to the different dialyticprocedures (SHD-CU or HDF-PAN), the use of sterile dialysate(phase 2) caused a significant decrease of predialysis TNF releasein both SHD CU patients (24.1±8.4 pg/ml versus 55.3±5.7pg/ml, P<0.001) and HDF PAN-treated patients (16.6±5.3pg/ml versus 29.1±5.4pg/ml, P<0.005), so that thedifferences between the dialytic procedures were completelyabolished. In conclusion, TNF and IL-6 release may be induced by endotoxin-contaminateddialysate during haemodialysis. The use of sterile bicarbonatecan ameliorate the bioincompatibility of CU membranes and probablyinfluences the biocompatibility of PAN membranes. Therefore,regardless of the type of dialyser used, all attempts to obtainan ultrapure dialysate are important to optimize dialytic treatment,in order to attenuate the chronic monocyte activation whichoccurs during haemodialysis.     

Effects of tumour necrosis factor alpha and interleukin-6 on progesterone and calcium ionophore-induced acrosome reaction

For human spermatozoa to successfully fertilize the oocyte, they need to undergo a timely acrosome reaction (AR). Factors which disturb the AR may lead to fertilization failure. The objective of this study was to investigate the effects of two cytokines namely tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) on the spontaneous, calcium ionophore-induced and progesterone-induced human sperm AR. Twenty-two normal semen samples were treated with increasing concentrations of TNF-α and IL-6 after spermatozoa were isolated by a double wash swim-up method. The AR was induced by calcium ionophore A23187 and progesterone. The AR was determined by using fluorescein isothiacyanate Pisum sativum agglutinin and observed under fluorescence microscope. Both TNF-α and IL-6 could decrease the spontaneous, ionophore and progesterone-induced AR ( p  <   0.05) in a dose-dependent manner. TNF-α showed a more potent inhibiting effect than IL-6 by inhibiting the AR at lower concentrations. This study has demonstrated that TNF-α and IL-6 play a role in inhibiting both the non-physiological as well as physiologically elicited AR by calcium ionophore and progesterone respectively.     

Elevated tumor necrosis factor alpha production concomitant to elevated prostaglandin E2 production by trauma patients' monocytes

The level of tumor necrosis factor alpha (TNF alpha), a monokine implicated in mediating septic shock, is elevated in the blood of some patients with sepsis. Monocytes from 11 trauma patients and 11 burn patients were suboptimally stimulated with interferon gamma and muramyl dipeptide, an analogue of bacterial wall products. The patients with sepsis showed significantly greater total TNF alpha levels (secreted in combination with cell-associated) 3 days before septic episodes, as compared with normal controls (32.38 to 2231.76 ng/10(6) monocytes per milliliter, median = 121.03 ng/10(6) monocytes per milliliter; normal control: 0.00 to 18.20 ng/10(6) monocytes per milliliter, median = 5.93 ng/10(6) monocytes per milliliter). Increases in patients' total monocyte TNF alpha levels greater than 30 ng/10(6) monocytes per milliliter correlated with septic episodes. In patients with sepsis, the total monocyte TNF alpha levels were increased despite a concomitant increase in their prostaglandin E2 levels in both stimulated (interferon gamma plus muramyl dipeptide) and unstimulated in vitro assays (9 patients: stimulated prostaglandin E2 range, 30.1 to 123.6 ng/10(6) monocytes per milliliter). Massively elevated monocyte TNF alpha and prostaglandin E2 production occurred simultaneously in patients with sepsis.     

Relative production of tumour necrosis factor alpha and interleukin 10 in adult respiratory distress syndrome

BACKGROUND: The adult respiratory distress syndrome (ARDS) may be regarded as an example of an uncontrolled or excessive inflammatory response in which tumour necrosis factor alpha (TNF-alpha) has been proposed to play a central role. Interleukin 10 (IL-10) has been identified as an important regulator of this response. The potential role for IL-10 in this context was investigated by measuring the relative production of IL-10 and TNF-alpha protein in the plasma, bronchoalveolar lavage (BAL) fluid, and alveolar macrophage culture supernatants of patients with, or at risk of developing, ARDS. METHODS: Twenty six patients were studied from three groups at risk of or with ARDS: sepsis (n = 12), multiple trauma (n = 8), and perforated bowel (n = 6). Ten patients had ARDS. Bronchoalveolar lavage and venepuncture were performed within 24 hours of arrival on the intensive therapy unit or of diagnosis of ARDS. IL-10 and TNF-alpha protein were detected in the plasma, BAL fluid, and alveolar macrophage supernatants by sandwich enzyme linked immunoabsorbent assays. RESULTS: The median IL-10 concentrations in the plasma and BAL fluid of patients with ARDS were significantly lower than the concentrations detectable in the plasma (median difference-17.5, 95% CI -52.4 to 1.31, p < 0.05) and BAL fluid of at risk patients (median difference -32.1, 95% CI -47.5 to 2.3, p < 0.05). There was a tendency towards enhanced concentrations of TNF- alpha detectable in the alveolar macrophage supernatants and the BAL fluid of patients with ARDS compared with at risk patients, although this did not reach statistical significance. No difference was observed in the plasma concentrations of TNF-alpha between the two groups. The ratios of TNF-alpha to IL-10 protein in the BAL fluid of patients with ARDS and at risk patients were 3.52 and 0.85, respectively (median difference 1.44, 95% CI 0.07 to 5.01, p < 0.01). There was no difference in alveolar macrophage production of IL-10 between the two groups. CONCLUSIONS: This study highlights the potential importance of the pro-inflammatory versus the anti-inflammatory imbalance in ARDS which may be reflected by the ratio of IL-10 and TNF-alpha in the lung.


     

Recovery of monocytes after bone marrow transplantation--rapid reappearance of tumor necrosis factor alpha and interleukin 6 production

After bone marrow transplantation many T-lymphocyte functions, including the production of cytokines (CK), such as interleukin 2, are severely depressed for months. The monocyte-derived cytokines tumor necrosis factor alpha and interleukin 6 are molecules central to immune functions. Moreover, they may be involved in graft-versus-host disease and in graft-versus-leukemia reaction. Hence, we have studied the reappearance of these CKs after BMT by analyzing whole blood cultures stimulated in vitro with lipopolysaccharide for 6 hr, followed by testing for the secretion of TNF in the WEHI 164/actinomycin D cytotoxicity bioassay and for IL-6 in the 7 TD 1 proliferation assay. We performed sequential studies in 6 children who were transplanted for aplastic anemia or leukemia with allogeneic bone marrow. We found that the production of both CKs can be induced as early as 10-14 days post BMT at the very beginning of engraftment, indicating that the regenerating monocyte system is recovering rapidly after BMT. Depletion and neutralization experiments confirmed that monocytes are the cellular source of the LPS-induced CK secretion after BMT. Control levels were reached 3 to 4 weeks post BMT. When analyzing the endotoxin-induced CK production in a larger panel of BMT patients after complete reconstitution, we could not detect any impact of acute or chronic GvHD, or of allogeneic or autologous BMT, nor did treatment with cyclosporine A (CsA) show any suppressive effect. Thus, our data show that the CK production of the monocyte/macrophage lineage is quite resistant to factors that do influence other cell lineages of the immune system during BMT. The coincident appearance of monocyte-derived cytokines and of GvHD suggests a role for these cytokines in GvHD in man.     

Effect of calcium-channel blocker on tumour necrosis factor alpha (TNF{alpha}) production in cyclosporin-treated renal transplant recipients

PURPOSE OF THE STUDY.: The influence of calcium-channel blocker treatment on in-vitroTNF production by peripheral blood mononuclear cells (PBMC)from renal transplant recipients treated with cyclosporin wasstudied. DESIGN.: We compared spontaneous and OKT3-induced TNF production of 12renal transplant recipients treated with calcium-channel blockertherapy with that of 18 renal transplant recipients who werenever treated with a calcium antagonist. RESULTS.: The two groups were similar with regards to age, time aftertransplantation, dosage of immunosuppressive drugs, and bloodcyclosporin levels. Spontaneous (481±161 versus 319±74pg/ml, n.s.) and OKT3-induced (745±182 versus 632±112pg/ml, n.s.) TNF production were similar in both groups. CONCLUSIONS.: The results indicate that in cyclosporintreated renal transplantrecipients calcium-channel blockers do not affect TNF production.     

Concomitant treatment of MBT-2 bladder tumour by tumour necrosis factor alpha and interferon alpha in conjunction with delayed type hypersensitivity immunotherapy

Summary In our previous study [9], we reported the anti-tumour effect of TNF on mouse bladder tumour (MBT-2) both in vivo and in vitro. Inoculation of a single dose of TNF alone caused significant but transient tumour growth inhibition. Subsequent repeated doses of TNF did not sustain or augment the antitumour effect. The current experiments were undertaken to assess the anti-tumour activity of (i)-concomitant treatment of TNF-A and IFN-A against MBT-2 bladder tumour and (ii)-concomitant TNF+IFN-A treatment in conjunction with T-DTH (delayed-type hypersensitivity) immunotherapy. Systemic administration of multiple doses of TNF+IFN-A in vivo caused initial partial tumour regression followed by tumour growth inhibition up to 14 days following treatment. This combined treatment showed an enhanced anti-tumour effect compared to TNF-A treatment alone. Immunotherapy of MBT-2 tumour-bearing mice with T-DTH immune effector cells alone did not cause significant tumour growth inhibition. In contrast, concomitant administration of both T-DTH effector cells and TNF+IFN-A in MBT-2 tumour-bearing mice resulted in significant tumour growth inhibition for up to 16 days. The immune effector cells conferring immunotherapy were isolated from the spleens of tumour-immunized, DTH-primed animals and were characterized as Lyt 1⁺2^- helper/DTH T cells (CD4⁺ phenotype). These cells mediate both DTH response to MBT-2 tumour antigens as well as anti-MBT-2 tumour protection. In vitro treatment of the immune cells with TNF-A resulted predominantly in the proliferation of Lyt 1⁺ T cells versus Lyt 2⁺ cells. The anti-tumour effect of TNF+IFN-A can be augmented by immunotherapy possibly via the immune capacity of tumour sensitized T-DTH effector cells.     

Decreased production of interleukin-1 by monocytes from patients with lipoid nephrosis

In order to further characterize monocyte function in patients with lipoid nephrosis (LN), we studied the production of interleukin-1 (IL-1). In this study we examined the ability of peripheral blood monocytes (PBM) from LN patients to produce this monokine in vitro under the stimulus of bacterial lipopolysaccharide (LPS). The levels of IL-1 were decreased in patients with LN compared with those in normal controls and lower in LN patients with nephrotic syndrome (NS) than in those without NS. In contrast, the values in IgA nephropathy (IgAN) patients with or without NS did not differ from normal subjects. The addition of indomethacin, an inhibitor of prostaglandin synthesis, partially restored this defect. These results suggest that the impaired IL-1 production of LN PBM is probably attributable, at least in part, to increased prostaglandin production and possibly influences the immune status of LN patients.     

Streptococcal exotoxin B increases interleukin-6, tumor necrosis factor alpha,interleukin-8 and transforming growth factor beta-1 in leukocytes

Previous reports have shown the presence of streptococcal erythrogenic exotoxin type B (ETB), leukocyte infiltration, interleukin-8 (IL-8), transforming growth factor-beta (TGF-β) and glomerular proliferation in renal biopsies from patients with acute post-streptococcal glomerulonephritis (APSGN). In addition, increased levels of plasma interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), and urinary IL-6, have also been reported in this disease. To determine the effect of streptococcal proteins on leukocyte proliferation and leukocyte production of IL-6, TNFα, IL-8 and TGF-β1, we cultured human mononuclear leukocytes with ETB or ETB precursor (ETBP). After 24 h, 48 h and 96 h, culture supernatants were assessed for cytokines by enzyme-linked immunosorbent assay (ELISA), and for leukocyte proliferation by a monoclonal antibody anti-proliferating cellular nuclear antigen (PCNA). A significant increase in all cytokines was found in ETB- or ETBP-treated cultures when compared with controls. A polyclonal anti-ETB antibody diminished the cytokine stimulatory effect of ETB. An increased number of PCNA-positive cells was observed in ETB or ETBP treated cultures at 48 h and 96 h. Cytokine production and proliferation were not correlated. The stimulatory effect of streptococcal exotoxin B on leukocyte cytokine production may be relevant in renal tissue during the course of APSGN.     

Serum tumour necrosis factor alpha and insulin resistance in gastrointestinal cancer.

Cancer cachexia may be mediated by endogenous peptides such as tumour necrosis factor alpha (TNF-alpha). Insulin resistance occurs in these patients, and is also seen experimentally with TNF-alpha administration. In this study, insulin sensitivity and energy metabolism were measured in 11 patients with gastrointestinal cancer and ten controls, using the euglycaemic glucose clamp and indirect calorimetry. Patients with cancer were significantly more insulin resistant than controls (P < 0.01) and in such patients insulin resistance correlated with serum TNF-alpha level (rs = 0.74, P < 0.01). Fasting insulin levels also correlated inversely with insulin sensitivity (rs = -0.62, P = 0.003). These results suggest a possible association between endogenous TNF-alpha production and insulin resistance in patients with gastrointestinal cancer.     

Effect of calcitriol on the secretion of prostaglandin E2, interleukin 1, and tumor necrosis factor alpha by human monocytes.

Cells of the monocyte/macrophage lineage express specific receptors for calcitriol (1,25-dihydroxyvitamin D3) and secrete prostaglandins and several cytokines with potent effects on bone metabolism. The aim of this study was to determine the effect of calcitriol on the secretion of prostaglandin E2 (PGE2), interleukin-1 (IL-1), and tumor necrosis factor (TNF alpha). Monocyte-enriched peripheral blood mononuclear cells (PBMC) from healthy subjects were cultured in the presence or absence of calcitriol (10(-11)-10(-7) M) and several stimulating agents. After 24 h, PGE2, IL-1, and TNF alpha were measured in the culture supernatants or lysates with specific immunoassays. Calcitriol induced a biphasic effect on PGE2 production by unstimulated cells and increased PGE2 synthesis by cells stimulated with either endotoxin or tau-interferon (IFN-tau). On the other hand, calcitriol inhibited the production of TNF alpha by monocytes stimulated with either IFN-tau or phorbol esters. This effect was not prevented by the addition of indomethacin, IL-1, or IL-2. Under the conditions used, we observed no effect of calcitriol on IL-1 alpha or IL-1 beta production. These results indicate that calcitriol induces in vitro marked changes in the secretion of monocyte products with known activity on bone cells. Further studies are needed to elucidate whether some effects of calcitriol on bone metabolism are mediated by the interaction of the sterol with cells of the immune system.     

Tumor necrosis factor and interleukin-1 protection against the lethal effects of tumor necrosis factor

Based on the hypothesis that tumor necrosis factor (TNF) causes the lethality of gram-negative sepsis and previous work of tolerance to the lethal effects of TNF induced by repetitive exposure to sublethal intraperitoneal doses of human recombinant (r) TNF, we studied the protective role of a single sublethal intravenous dose of either rTNF (100 micrograms/kg) or recombinant interleukin-1 (rIL-1; 10(5) units/kg) or both before a subsequent lethal intravenous dose of rTNF (800 to 1000 micrograms/kg) in C3H/HEN mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF. Mice treated with rTNF showed significant protection against the lethal effects of TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal protection required a 24-hour interval and lasted as long as 8 days. The treatment dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated with rIL-1 showed maximal protection when treatment was given only 2 hours before challenge and protection lasted for 8 days. No toxicity was apparent secondary to IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention and treatment of sepsis lethality by the induction of tolerance to the lethal effects of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity and more rapid induction of full therapeutic effectiveness.     

Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma

BACKGROUND: Inhaled tumour necrosis factor alpha (TNF alpha) has previously been shown to induce airway neutrophilia and increased airway reactivity in normal subjects. It was hypothesised that a similar challenge would increase airway reactivity in those with mild asthma, but that the inflammatory profile may differ. METHODS: Ten mild asthmatic subjects were recruited on the basis of clinical asthma and either a sensitivity to methacholine within the range defined for asthma or a 20% improvement in forced expiratory volume (FEV(1)) after 200 micro g salbutamol. Subjects inhaled either vehicle control or 60 ng recombinant human (rh)TNF alpha and were studied at baseline, 6, 24, and 48 hours later. Variables included spirometric parameters, methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)), induced sputum differential cell count, relative sputum level of mRNA of interleukins (IL)-4, IL-5, IL-9, IL-14, IL-15 and TNF alpha, and the exhaled gaseous markers of inflammation, nitric oxide and carbon monoxide. RESULTS: PC(20) showed an increase in sensitivity after TNF alpha compared with control (p<0.01). The mean percentage of neutrophils increased at 24-48 hours (24 hour control: 1.1 (95% CI 0.4 to 2.7) v 9.2 (95% CI 3.5 to 14.9), p<0.05), and there was also a rise in eosinophils (p=0.05). Relative levels of sputum mRNA suggested a rise in expression of TNF alpha, IL-14, and IL-15, but no change in IL-4 and IL-5. Spirometric parameters and exhaled gases showed no significant change. CONCLUSION: The increase in airway responsiveness and sputum inflammatory cell influx in response to rhTNF alpha indicates that TNF alpha may contribute to the airway inflammation that characterises asthma.     

Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury

The brain is no longer considered immune-privileged due to its capability of producing cytokines in response to neurotrauma; however, the cellular sources of cytokines have not been defined. This study focused on the production of four inflammatory cytokines, interleukin-1 (IL-1alpha), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interferon gamma (IFN-gamma) in primary culture of astrocytes under two different injury models which simulated in vivo mechanical trauma (scratch injury) and ischemia. Results demonstrated that astrocytes after scratch injury were positively immunostained with IL-1alpha, IL-6, and TNFalpha. A slot-blot study of culture media showed that the release of IL-1alpha, IL-6, TNFalpha, and IFN-gamma by astrocytes subsequent to scratch and ischemic injury reached approximately twice the control values. The temporal expression of these cytokines was different for the two models. All four cytokines began to increase 1 h postscratch and remained at high levels throughout the experiment. In the ischemic model, however, the increase of cytokine expression was delayed until 4-8 h of ischemia, when sharp increases were seen in all four cytokines. In this culture system, the exogenous influence of blood-borne factors and leukocytes, which occur with in vivo trauma and ischemia, was eliminated. Accordingly, the cytokines detected in the culture media were derived from astrocytes. This study provides the first evidence that astrocytes, without the influence from other cell types, can produce and release cytokines following mechanical and ischemic injury.     

Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype

BACKGROUND: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor alpha (TNFalpha), a member of the immune system. METHODS: Three polymorphic loci in the promoter (-851c/t, -308g/a, -238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFalpha gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records. RESULTS: An association was found between the TNFalpha +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the -851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the -851c allele than in the other group of patients (p = 0.04, likelihood ratio chi2, odds ratio = 2.4). CONLUSION: TNFalpha polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.     

Prolongation of skin allografts by recombinant tumor necrosis factor and interleukin-1.

OBJECTIVE: The hypothesis is that systemic administration of recombinant tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleukin-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft. SUMMARY BACKGROUND DATA: Tumor necrosis factor and IL-1 are pluripotent cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced by systemic administration of recombinant cytokines. The authors previously have demonstrated that pretreatment with cytokines such as IL-1 or TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram-negative sepsis, cancer cachexia, and oxygen toxicity. METHODS: Skin grafts from the tails of Balb/c mice were placed on the backs of C57Bl/6 mice. Mice were treated with daily intraperitoneal saline, recombinant m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoche, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necrosis factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kaplan-Meier plot and analyzed by the log-rank test. Comparison of proportions was done using the Fisher's exact test. RESULTS: Either TNF or IL-1 alone significantly prolonged skin graft survival compared with saline control. Furthermore, the combination of TNF and IL-1 prolonged skin graft survival longer than either cytokine alone. Mice on the highest dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cytokine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1. CONCLUSION: Both TNF and IL-1 can be effective as suppressors of skin allograft rejection in mice.