A chronic model for experimental investigation of epidural anesthesia in the rabbit

BACKGROUND/AIMS: By contrast with animal models, in most cases it is not possible to examine the systemic response in patients in the first hours after onset of acute pancreatitis. The aim was to determine whether endoscopic retrograde cholangiopancreaticography (ERP)-induced pancreatitis can be used as a human model for the study of cytokine release and acute phase response in the first hours of the disease. PATIENTS AND METHODS: Seventy consecutive patients undergoing ERP for different reasons were prospectively evaluated by sampling blood before and 0, 1, 4, 12, 24, and 48 hours after ERP and, in patients who developed an acute post-ERP pancreatitis, daily until C reactive protein (CRP) was within normal range. A post-ERP pancreatitis was defined as a three-fold increase of amylase or lipase and at least two of the clinical symptoms: abdominal pain, nausea, vomiting, and peritonism during 24 hours after ERP. RESULTS: Nine out of 70 patients developed an acute pancreatitis. Cytokines and other biochemical variables were measured in those nine and in 34 patients out of the 61 not developing pancreatitis. In the nine patients amylase and lipase increased within the first hour after ERP with maximum values between four and 12 hours. Interleukin-6 increased to maximal concentrations after 24-48 hours and the highest CRP concentrations were found 72 hours after ERP. Tumour necrosis factor did not change. CONCLUSION: Post-ERP pancreatitis is an ideal model in which to examine the initial cytokine and acute phase response in the first hours after the initiation of the disease.     

The role of cytokines in Henoch Schonlein purpura

Serum levels of tumor necrosis factor (TNF) and interleukin(IL-1) were studied in 20 HSP patients, in the acute phase and after remission, by ELISA technique. Skin biopsies obtained during the acute phase both from a lesion and from unaffected skin, as well as during remission, were immunostained for TNF, IL-1, and IL-6. The mean age of the patients was 9.8 (5-13). Mean serum TNF levels during the acute phase and remission were 14.0 +/- 8.9 pg/ml, and 6.8 +/- 2.4 pg/ml, respectively (p < 0.05). Serum TNF levels in patients with renal involvement (18.8 +/- 10.2 pg/ml) were significantly higher than in those without (10.8 +/- 6.5 pg/ml) (p < 0.05). Serum levels of IL-1 in the acute phase and remission were undetectable. All specimens showed leukocytoclastic vasculitis. Immunohistochemical studies revealed TNF, and a less intense IL-1 and IL-6 staining in the nucleated epidermal layer, with a granular, intracellular pattern. Staining was significantly increased in the affected skin during the acute phase. These results suggest that TNF, IL-1, and IL-6 may play a role as a mediator of inflammation in HSP.     

Plasma levels of TNF and IL-6 following induction of acute pancreatitis and pentoxifylline treatment in rats

Activation of cytokine cascade is a decisive factor in determining the pathobiology of different inflammatory processes including acute pancreatitis. The purposes of this study were to determine the TNF and IL-6 levels after the induction of acute necrotizing pancreatitis, and to establish the effects of pentoxifylline on the cytokine production and the severity of pancreatitis. Acute necrotizing pancreatitis was induced by the retrograde injection of 200 microliters taurocholic acid into the pancreatic duct in male Wistar rats. TNF was titrated in a bioassay on cell line WEHI clone 164. IL-6 was measured via its proliferative action on the IL-6 dependent mouse hybridoma cell line B-9. Seven mg/kg pentoxifylline was administered intraperitoneally at the time of operation and/or 24 hours later. Rats were sacrificed, 48 or 72 hours after the operation. The TNF bioassay revealed high levels of TNF (36.6 +/- 6.0 U/ml) in the control group whereas levels decreased to zero in the pentoxifylline-treated group. The IL-6 bioassay likewise demonstrated high levels of IL-6 in the control group and markedly decreased levels in the pentoxifylline treated group (7083 +/- 2844 pg/ml, 6463 +/- 1307 pg/ml vs. 137.5 +/- 85.5 pg/ml, respectively, p < 0.05). The high mortality observed in the control group (43%) was sharply decreased by pentoxifylline administration to 11%. The data suggest that pentoxifylline is capable of modifying the cytokine production after 48 hours of induction of acute pancreatitis.     

Reduced production of immunoreactive interleukin-1 by peripheral blood monocytes of patients with acute and chronic viral hepatitis

The in vitro production of interleukin-1 beta by peripheral blood monocytes derived from patients with various liver diseases was studied. An impaired production of immunoreactive interleukin-1 (IL-1) (mean +/- SEM) by monocytes stimulated with an optimal dose (100 ng/ml) of lipopolysaccharide was observed in patients with chronic hepatitis B (N = 13; 32 +/- 6 pg/ml) or chronic hepatitis C (N = 13; 61 +/- 12 pg/ml) as compared to those of healthy control individuals (N = 35; 166 +/- 24 pg/ml; P = 0.0003 and P = 0.015, respectively), whereas an unaltered IL-1 production was seen in patients with alcoholic cirrhosis (N = 23; 125 +/- 28 pg/ml) and primary biliary cirrhosis (N = 6; 111 +/- 33 pg/ml). Similar to the situation seen in chronic viral hepatitis, lipopolysaccharide-stimulated monocytes from patients with acute hepatitis also showed a decreased IL-1 production in the first week after onset of jaundice (N = 17; 55 +/- 20 pg/ml; P = 0.001) and a return to normal in the second and third week. An impaired production of IL-1 in chronic as well as acute viral hepatitis is a further example of the known disturbed immunoregulation in this disease.     

Synchrony in telomere length of the human fetus

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.     

Elevation of cyclic adenosine 3',5'-monophosphate potentiates activation of mitogen-activated protein kinase by growth factors in LNCaP prostate cancer cells

OBJECTIVE: Proinflammatory cytokines are involved in the pathogenesis of acute pancreatitis. The value of serum levels of tumor necrosis factor-alpha, interleukin-1-beta, interleukin-6, and interleukin-8 in predicting the outcome of acute pancreatitis was evaluated. METHODS: In 50 patients with acute pancreatitis, the serum concentrations of tumor necrosis factor-alpha, interleukin-1-beta, interleukin-6, interleukin-8, and C-reactive protein were determined on days 1, 2, 3, 4, and 7 after admission. Acute Physiology and Chronic Health Evaluation (APACHE II) scores were recorded on days 1, 2, and 3. RESULTS: Serum concentrations of interleukin-1-beta, interleukin-6, interleukin-8, and C-reactive protein on days 1-7 were significantly higher in patients with severe pancreatitis than in patients with mild pancreatitis. Patients with severe attacks had significantly elevated serum tumor necrosis factor-alpha concentrations on days 1-3 compared with those with mild attacks, but not on days 4 and 7. The median peak value of tumor necrosis factor-alpha, interleukin-1-beta, interleukin-6, and interleukin-8 was reached on day 1, in contrast to the median peak of C-reactive protein, which was reached on day 2. Using cutoff levels of 12 pg/ml for tumor necrosis factor-alpha, 1 pg/ml for interleukin-1-beta, 400 pg/ml for interleukin-6, 100 pg/ml for interleukin-8, 12 mg/dl for C-reactive protein, and 10 for the Acute Physiology and Chronic Health Evaluation (APACHE II) score, the accuracy rates for detecting severe pancreatitis were 72%, 82%, 88%, 74%, 80%, and 72%, respectively, on day 1 and 78%, 74%, 80%, 76%, 80%, and 78%, respectively, on day 2. CONCLUSION: Among the proinflammatory cytokines, interleukin-6 is the most useful parameter for early prediction of the prognosis of acute pancreatitis.     

A spontaneous induction of fetal membrane prostaglandin production precedes clinical labour

Fetal membranes from term human pregnancies produce prostaglandins, and may respond to bacterial endotoxin or interleukin-1 beta (IL-1 beta) with increased prostaglandin E2 (PGE2) production. The effects of endotoxin persisted for up to 24 h, whereas those of IL-1 beta were maximal 4-8 h after addition. The maximum levels of PGE2 (200-350 pg/ml) were similar in all experiments, and were independent of the stimulus used. Not all tissues responded to these stimuli; those which did not had basal levels of PGE2 production of 200-350 pg/ml, which was not further increased by endotoxin or IL-1 beta. The basal production from these tissues was therefore similar to the maximal production from those tissues which responded to endotoxin or IL-1 beta. The high basal production of PGE2 was attributed to prior in vivo activation of the membranes such that PGE2 synthesis could not be further stimulated in vitro. Overnight pretreatment with aspirin decreased basal PGE2 production from these activated membranes to < 100 pg/ml/4 h during subsequent culture in aspirin-free medium. Both endotoxin and IL-1 beta increased PGE2 production from the activated aspirin-pretreated membranes during this culture time, but this was transient as after 12 h of culture basal PGE2 production rose to over 200 pg/ml despite aspirin pretreatment.     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Leukemia inhibitory factor modulates interleukin-1beta-induced activation of the hypothalamo-pituitary-adrenal axis

We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1beta (IL-1beta; 0.1-10.0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h, and still persistently elevated above the baseline after 8 h. This effect of IL-1beta on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1beta antibody (10 microg/ml). Tumor necrosis factor-alpha (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1beta (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, i.p. injection of 100 ng IL-1beta increased plasma ACTH and corticosterone levels after 1 h (P < 0.02). In addition, pituitary LIF mRNA content was increased for up to 2 h in response to IL-1beta. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a deleted LIF gene (-/-) exhibited decreased plasma ACTH (631 +/- 61 vs. 376 +/- 50 pg/ml; P < 0.01) and corticosterone (783 +/- 85 vs. 433 +/- 51 ng/ml; P < 0.01) levels 1 h after i.p. IL-1beta administration. In conclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1beta and tumor necrosis factor-alpha. The attenuated hypothalamo-pituitary-adrenal response to IL-1beta in LIF knockout mice indicates that the effect of IL-1beta on ACTH secretion is modulated by LIF. Thus, LIF appears to function as an immune-neuroendocrine modulator signaling the hypothalamo-pituitary-adrenal axis.     

Cytokines in vitreous humor: interleukin-6 is elevated in proliferative vitreoretinopathy

PURPOSE: To measure the levels of interleukins (IL) 1 beta, 6, and 8, and tumor necrosis factor-alpha (TNF alpha) in the vitreous of patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), vitreous hemorrhage, and macular pucker. METHODS: Vitreous samples were collected, undiluted, from patients with PVR, PDR of varying severity, and miscellaneous lesions (vitreous hemorrhage from trauma, macular degeneration, vein occlusion, and non-PVR patients with giant tear, retinal detachment, and macular pucker). Immunoreactive levels of the cytokines, IL-1 beta, IL-6, IL-8, and TNF alpha were determined by enzyme-linked immunoadsorbent assays, and samples were analyzed for protein and hyaluronic acid content using standard assays. RESULTS: The levels of TNF alpha were below detection limits of the assay (< 3 pg/ml). In 45 of the 47 samples tested, IL-1 beta levels also were below detection limits of the assay (< 3 pg/ml). IL-6 levels ranged from < 30 to 5487 pg/ml, with the highest values observed in the PVR patients. IL-8 levels ranged from < 20 to 1900 pg/ml, and were consistently high in the miscellaneous group. Some of the PVR patients with C2 and C3 level severity also exhibited IL-8 levels exceeding 100 pg/ml. In a second study, IL-6 content of vitreous from miscellaneous and PVR patients was compared. In this study, significantly elevated levels of IL-6 were observed in the PVR patients (91.5 +/- 18 pg/ml) compared to the miscellaneous group (10.3 +/- 3.7 pg/ml) CONCLUSIONS: Elevated levels of IL-6 in the vitreous occur in PVR, implicating a role for this cytokine in the pathogenesis of this ocular disorder.     

Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis

BACKGROUND & AIMS: During severe pancreatitis, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are produced in large quantities. The aim of this study was to determine whether either one plays a more dominant role and if their detrimental effects are additive. METHODS: Necrotizing pancreatitis was induced in transgenic (-/-) knockout mice deficient in either IL-1 type 1 receptors, TNF type 1 receptors, or both IL-1 and TNF type 1 receptors. Wild-type mice served as controls. Mortality was assessed for 10 days. Additional animals were killed on days 0, 1, 2, 3, and 4 for determination of pancreatitis severity. RESULTS: All three knockout groups showed decreased amylase and lipase, histological score, serum IL-6, and mortality compared with wild-type groups. Animals devoid of receptors for both cytokines showed improved survival and decreased IL-6 levels compared with those devoid of either IL-1 or TNF receptors individually, yet they failed to show a further decrease in pancreatitis severity. CONCLUSIONS: Preventing the activity of IL-1beta or TNF-alpha has a nearly identical beneficial effect on the severity and mortality of acute pancreatitis. Preventing the activity of both cytokines concurrently has no additional effect on pancreatitis severity but further attenuates the systemic stress response and is associated with an additional but modest decrease in mortality.     

The "interleukin 1 receptor antagonist" is a partial agonist of prostaglandin synthesis by human decidual cells

In many systems the interleukin-1 receptor antagonist opposes the effects of interleukin-1 beta. We considered that it might block interleukin-1 beta-stimulated prostaglandin production from human decidual cells. Very high levels of interleukin-1 receptor antagonist (> 1000 pg/ml) had limited inhibitory effects on IL-1 beta-stimulated PGE2 synthesis, and lower levels of antagonist (< 1000 pg/ml) increased the effects of IL-1 beta. Low concentrations of the antagonist alone (1-100 pg/ml) increased basal PGE2 production, whereas higher levels (10-100 ng/ml) had less effect. It seems, therefore, that in human decidua the "antagonist" is more accurately described as a partial agonist. It has been suggested that the IL-1 receptor antagonist could be used to inhibit decidual prostaglandin synthesis and thereby prevent preterm labor, but this report shows that caution should be exercised before using the receptor antagonist.     

Distribution of IgG subclasses in antimonial unresponsive Indian kala-azar patients

BACKGROUND: Interleukin 10 (IL-10) decreases the severity of experimental acute pancreatitis. The role of endogenous IL-10 in modulating the course of pancreatitis is currently unknown. AIMS: To examine the systemic release of IL-10 and its messenger RNA production in the pancrease, liver, and lungs and analyse the effects of IL-10 neutralisation in caerulein induced acute pancreatitis in mice. METHODS: Acute necrotising pancreatitis was induced by intraperitoneal caerulein. Serum levels of IL-10 and tumour necrosis factor (TNF), and tissue IL-10 and TNF-alpha gene expression were assessed. After injecting control antibody or after blocking the activity of endogenous IL-10 by a specific monoclonal antibody, the severity of acute pancreatitis was assessed in terms of serum enzyme release, histological changes, and systemic and tissue TNF production. RESULTS: In control conditions, serum IL-10 levels increased and correlated with the course of pancreatitis, with a maximal value eight hours after induction. Both IL-10 and TNF-alpha messengers showed a similar course, and were identified in the pancreas, liver, and lungs. Neutralisation of endogenous IL-10 significantly increased the severity of pancreatitis and associated lung injury as well as serum TNF protein levels (+75%) and pancreatic, pulmonary, and hepatic TNF messenger expression (+33%, +29%, +43%, respectively). CONCLUSIONS: In this non-lethal model, systemic release of IL-10 correlates with the course of acute pancreatitis. This anti-inflammatory response parallels the release of TNF and both cytokines are produced multisystemically. Endogenous IL-10 controls TNF-alpha production and plays a protective role in the local and systemic consequences of the disease.     

Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients

Plasma endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 1 receptor antagonist (IL-1ra), and interleukin 6 (IL-6) concentrations in 69 bacteremic patients were compared with those in 54 nonbacteremic patients suffering from suspected bacterial infections. Only three (11%) of the 27 patients with gram-negative bacteremia showed detectable levels of endotoxin. TNF-alpha was detected in 6% of the bacteremic patients and in none of the nonbacteremic patients. Median IL-6 levels were significantly higher in bacteremic than in nonbacteremic patients (55 vs. 0 pg/ml, p = 0.0008). IL-6 concentrations were similar in neutropenic and non-neutropenic bacteremic patients (median 55 vs. 74 pg/ml). In contrast, neutropenic bacteremic patients had significantly lower concentrations of IL-1ra than non-neutropenic bacteremic patients (250 vs. 1,950 pg/ml, p < 0.0001). Patients with fatal bacteremia had significantly higher concentrations of IL-6 and IL-1ra than the survivors (median, 450 vs. 40, p = 0.012 and 7,600 vs. 420 pg/ml, p = 0.0075, respectively). Determinations of endotoxin or TNF-alpha in patients with suspected bacteremia failed to offer clinically relevant data on the prognosis of these patients. IL-6 levels correlated with both the presence of bacteremia and the risk of death. Granulocytopenic patients with bacteremia had lower levels of circulating IL-1ra than patients with normal granulocyte counts, and these levels correlated with poor outcome.     

Interleukin 1 beta, but not tumor necrosis factor, enhances neurogenic vasodilatation in the rat skin: involvement of nitric oxide

In phenobarbitone-anesthetized rats the effects of interleukin 1 beta (IL-1 beta) and tumor necrosis factors (TNFs) were examined on the capsaicin-induced increase of plantar cutaneous blood flow in the rat hind paw as measured by laser Doppler flowmetry. IL-1 beta (0.5-500 pg) or TNF alpha or TNF beta (50-500 pg) was injected subcutaneously into the left paws, while the right paws received vehicle (10 microL) only. IL-1 beta was without effect on blood flow by its own but dose dependently enhanced the hyperemia due to capsaicin (0.3 microgram). TNFs failed to enhance the capsaicin-induced vasodilatation although 5000 pg TNF alpha produced a transient increase of local blood flow. Indomethacin (10 mg/kg, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1 beta (50 pg) from augmenting the hyperemic response to capsaicin. Likewise, blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester (L-NAME) failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by IL-1 beta. Systemic pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-induced hyperemia and prevented the facilitatory effect of IL-1 beta. The hyperemia evoked by intraplantar calcitonin gene related peptide (0.038-3.8 ng) was not altered by IL-1 beta (50 pg). These data indicate that IL-1 beta but not TNF enhances the cutaneous hyperemic response to capsaicin. This proinflammatory action arises from sensitization of afferent nerve endings and depends on nitric oxide and cyclooxygenase products as essential intermediates.     

Bacillus Calmette-Guérin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients

During the past decade, particular attention has been focused on treatment of bladder cancer patients with the bacterial agent bacillus Calmette-Guérin (BCG). In these studies, bladder cancer patients were instilled with BCG (75 mg/50 ml) once per week for 6 weeks, 1-2 weeks following trans-urethral resection of the bladder. Cystoscopy was performed after 6 weeks and, unless tumor progression was present, monthly treatments were given for 1 year. Blood was drawn 2 h after the last instillation, and monocytes were isolated (5 x 10(6) cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 microgram/ml) for tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Our results clearly show that, after 18 h incubation, macrophages from BCG-treated bladder cancer patients produced from 2.8- to 1.9-fold and from 2.0- to 1.3-fold greater amounts of TNF alpha and IL-1 alpha respectively, compared to macrophages from healthy controls, 5-fold higher than bladder cancer patients not treated with BCG. IL-6 was not affected. In another set of experiments macrophages (5 x 10(6) cells/ml) from healthy subjects were pretreated, or not, with BCG (100 micrograms/ml) overnight and treated, or not, with LPS 20 microgram/ml alone and in combination with interleukin-1 receptor antagonist (IL-1ra) 250 ng/ml. Macrophages treated with BCG had a strong stimulatory effect on IL-1 alpha release (9.45 ng/ml) while LPS was less effective (3.59 ng/ml). The combination of BCG plus LPS produced an additive effect on IL-1 alpha release (13.71 ng/ml) compared to the effect of the compound alone. The addition of IL-1ra (250 ng/ml) to BCG was not effective, while when IL-1ra was added to BCG plus LPS only a partial inhibition of IL-1 alpha release was found (9.83 ng/ml), compared to BCG plus LPS without IL-1ra (13.71 ng/ml). These effects seem to be related to the inhibition of IL-1 alpha stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNF alpha and IL-1 alpha from bladder cancer patients led us to study the possible modulation of fibrinogen and C-reactive protein in the serum of BCG-treated cancer patients. The plasma levels of fibrinogen and C-reactive protein were higher (approximately twice) in BCG-treated patients compared to values obtained in untreated patients or healthy controls. We conclude that the beneficial immunotherapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to enhance the release of TNF alpha and IL-1 alpha, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-1 alpha or TNF alpha, which are directly involved in the killing of cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)