Cerebrospinal Fluid TNF-α Research Articles

Serum and cerebrospinal fluid cytokine concentrations in subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disease due to persistent measles virus infection. Its immunopathogenesis is unknown. Tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-10 and IL-4 concentrations were measured in cerebrospinal fluid (CSF) and serum samples from 30 SSPE patients and 19 control subjects by cytometric bead array. CSF and serum IFN-γ, IL-12 and IL-18 levels were measured in 18 SSPE patients by ELISA. Serum IL-4 and IL-10 ( p < 0.001), CSF IL-4 ( p < 0.001) and IL-6 ( p = 0.049) concentrations were lower, and serum IL-2 concentrations, higher ( p = 0.001) in SSPE patients. Serum TNF-α and IL-6, CSF TNF-α, IL-10, and IL-2 concentrations were not different between SSPE and control groups. Serum IFN-γ levels were higher in stage I and II than stage III patients ( p < 0.05), whereas there was no difference between stages in terms of other cytokines. The levels of Th2-type cytokines: IL-4, IL-6 and IL-10 were suppressed in our SSPE cases. This finding, along with relatively elevated IFN-γ and IL-2 levels, may suggest more active effector T cells compared to regulatory T cells (Treg), especially induced Treg, in early disease. High serum IL-2 concentrations might indicate peripheral Th1 activation. Discrepancies between various reports in the literature should be examined in view of the ages, stage and treatments of the patients studied. The interplay of various cytokines or cellular systems which may vary over time and between patients. Studies of treatment measures favoring the preservation of the early inflammatory response may be of interest in SSPE.

Effects of Toll-like receptor 2 agonist Pam 3CysSK 4 on inflammation and brain damage in experimental pneumococcal meningitis

TLR2 signaling participates in the pathogenesis of pneumococcal meningitis. In infant rats, the TLR2 agonist Pam 3CysSK 4 was applied intracisternally (0.5 μg in 10 μl saline) alone or after induction of pneumococcal meningitis to investigate the effect of TLR2 activation on cerebrospinal fluid (CSF) inflammation and hippocampal apoptosis. A dose effect of Pam 3CysSK 4 on apoptosis was investigated by intracisternal application of 0.5 μg in 10 μl saline and 40 μg in 20 μl saline. Pam 3CysSK 4 neither induced apoptosis in sham-operated mice nor aggravated apoptosis in acute infection. However, Pam 3CysSK 4 induced pleocytosis, TNF-α and MMP-9 in CSF in sham-infection but not during acute meningitis. We conclude that TLR2 signaling triggered by Pam 3CysSK 4 at a dosage capable to induce a neuroinflammatory response does not induce hippocampal apoptosis in the infant rat model of experimental pneumococcal meningitis.

Circulating B7-H3(CD276) Elevations in Cerebrospinal Fluid and Plasma of Children with Bacterial Meningitis

The objective of this study was to analyze the clinical significance of cerebrospinal fluid (CSF) and plasma concentrations of B7-H3, tumor necrosis factor-alpha (TNF-alpha), gamma interferon (IFN-gamma), and interleukin-17 (IL-17) in bacterial and aseptic meningitis in children. The participants were six children with bacterial meningitis, 16 with aseptic meningitis, and 12 control subjects. All participants were between 2 months and 12 years of age on admission. Cytokines determination was performed by enzyme-linked immunosorbent assay technique. CSF and plasma-circulating B7-H3 were significantly higher in the bacterial meningitis group as compared with the aseptic group (p = 0.001) and the control group (p = 0.000 and p = 0.001 respectively). However, CSF and plasma-circulating B7-H3 in aseptic meningitis were not significantly higher than control group (p = 0.071 and p = 0.72 respectively).CSF and plasma-circulating TNF-alpha were significantly higher in the bacterial meningitis group as compared with the aseptic group (p = 0.004 and p < 0.0001 respectively) and control group (p = 0.004 and p < 0.0001 respectively). Similarly, we did not observe significant elevated TNF-alpha levels in CSF and plasma in aseptic group compared with control group (p = 0.03 and p = 0.12 respectively). IFN-gamma levels in CSF and plasma were undetectable in control group, and we did not find statistical significances in both of CSF and plasma between the elevated IFN-gamma level in bacterial meningitis group and aseptic meningitis group(p = 0.055 and p = 0.095 respectively) CSF and plasma levels of IL-17 were undetectable in all subjects. There were correlations between B7-H3 and TNF-alpha, IFN-gamma (r = 0.875, p = 0.000; r = -0.693, p = 0.000, respectively) in CSF in meningitis subjects. In plasma, levels of B7-H3 in bacterial meningitis on admission correlated positively with TNF-alpha (r = 0.968, p = 0.002), and white blood cell counts (r = 0.973, p = 0.001). Detectable CSF levels of B7-H3, TNF-alpha, and IFN-gamma on admission were not associated significantly with any of CSF characteristics. Additionally, CSF and plasma levels of B7-H3 decreased remarkably after treatment. Altogether, our data indicated that circulating B7-H3 and TNF-alpha levels in the CSF and plasma were useful markers for distinguishing bacterial from aseptic meningitis, and Circulating B7-H3 was demonstrated to be useful in evaluating the intensity of the infectious inflammatory process in the central nervous system in children.

Cerebrospinal fluid IL-6, HSP72, and TNF-α in exercising humans

During exercise the concentration of interleukin (IL)-6 and of heat shock protein (HSP) 72 increases in plasma, especially in fasting subjects. Both IL-6 and HSP72 are involved in a variety of metabolic and immunological processes, including some within the central nervous system and, accordingly, they are present not only in plasma but also in the cerebrospinal fluid (CSF). To evaluate whether, the two pools equilibrate we determined the levels of IL-6 and HSP72 in CSF, at a time when their plasma levels were increased due to exercise. Measurements of TNF-α served as a control, as its plasma level remains stable during exercise. Two groups of healthy, fit males performed 2 h of strenuous exercise with either carbohydrate ingestion ( n = 8) or placebo ( n = 8). The concentration of IL-6, HSP72, and TNF-α was measured in arterial blood and in the CSF obtained by a lumbar puncture immediately after exercise. A third group of subjects served as resting controls ( n = 8). At rest, CSF levels of IL-6 and HSP72 were 2- and 3-fold higher than the plasma levels, respectively ( P < .05). During exercise, with and without carbohydrate ingestion, plasma IL-6 increased 8- and 18-fold, respectively, and HSP72 increased 5-fold ( P < .05). However, the concentrations of IL-6 and HSP72 in CSF did not change with exercise and were therefore below their corresponding plasma levels. The concentration of TNF-α in CSF was below that in plasma and both remained stable during exercise. The findings that resting CSF levels of IL-6 and HSP72 are higher than in plasma and that they remain stable despite exercise-induced, profound increases in their systemic levels, suggest that the CSF pool is segregated from that in blood.

Analysis of serum and cerebrospinal fluid cytokine levels in subacute sclerosing panencephalitis in Papua New Guinea

Background Subacute sclerosing panencephalitis (SSPE) is a rare progressive inflammatory disease characterized by the persistent infection of the brain by the measles virus. However, the immunological pathophysiology of SSPE is still unclear. Methods We measured the concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in the serum and cerebrospinal fluid (CSF) of 23 patients with SSPE in Papua New Guinea (PNG), a country with a high incidence of SSPE, and Japanese controls by cytometric bead array or ELISA. Results The serum IL-6 and IL-10 levels of SSPE patients were significantly higher than those of controls ( p = 0.0075, and p = 0.0019, respectively). The serum IL-6 and IL-10 levels of SSPE patients with fever were significantly higher than those without fever ( p = 0.0107, and p = 0.0006, respectively). The CSF IL-6 levels of SSPE patients were significantly higher than those of controls ( p = 0.0218). The CSF IL-6 levels of SSPE patients with myoclonic jerks were significantly higher than those without myoclonic jerks ( p = 0.0189). There were no differences in serum IFN-γ, TNF-α, IL-2, IL-4, and sTNFR1, or CSF IFN-γ, TNF-α, IL-2, IL-4, IL-10, and sTNFR1 levels between the affected patients and controls. Conclusion Our present study suggests that serum IL-6 and IL-10 levels are related to fever, and the CSF IL-6 level, myoclonic jerks, in SSPE patients in PNG.

Cerebrospinal fluid tau, Aβ 1–42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia

In this study we aimed to evaluate the possibility of using cerebrospinal fluid (CSF) tau, Aβ 1–42 and inflammatory cytokines for diagnosis of Alzheimer's disease (AD) and vascular dementia (VD). We measured levels of total tau (T-tau), phospho-tau (P-tau), Aβ 1–42, IL-6, and TNFα in CSF in groups of AD, VD, and controls using enzyme-linked immunosorbent assay (ELISA). T-tau level was found significantly higher in groups of AD ( t = 3.015, P < 0.01) and VD ( t = 2.872, P < 0.01) than in controls. IL-6 level as also higher in AD ( t = 2.883, P < 0.01) and VD ( t = 3.032, P < 0.01) than in controls. Both T-tau and IL-6 were not significantly different between AD and VD ( P > 0.05). The group of AD had remarkably higher P-tau ( t = 4.261 and 3.883, respectively, P < 0.01) and lower Aβ 1–42 ( t = 3.883 and 4.129, respectively, P < 0.01), as compared with those in VD and controls. TNFα level in AD was significantly higher than that in controls ( t = 2.745, P < 0.01), but lower than in VD ( t = 3.032, P < 0.01). Our data suggested that increment of T-tau and IL-6 levels in CSF was useful for screening AD and VD in certain population, while descending Aβ 1–42 and ascending TNFα in CSF are preferable to diagnose AD. In addition, a higher level of CSF P-tau might support AD diagnosis.

IFN-γ at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Autoimmune-induced damage of the midbrain dopaminergic system in lupus-prone mice

Spontaneous development of lupus-like disease is accompanied by impaired dopamine catabolism and degenerating axon terminals in the mesencephalon of MRL-lpr mice. We presently examine the hypothesis that systemic autoimmunity affects the central dopaminergic system in behaviorally impaired animals. The functional damage of the nigrostriatal pathway was assessed from rotational behavior after a single injection of the D1/D2-receptor agonist apomorphine. Neurodegeneration in the midbrain was estimated by Fluoro Jade B (FJB) staining. The causal role of autoimmunity was tested by comparing asymptomatic and diseased MRL-lpr mice, and by employing the immunosuppressive drug cyclophosphamide. Damage of dopaminergic neurons was assessed by tyrosine-hydroxylase (TH) staining of the midbrain. Apomorphine induced significant asymmetry in limb use, which lead to increased circling in the diseased MRL-lpr group. While FJB-positive somas were not seen in the striatum, increased staining in the substantia nigra (SN) and ventral tegmental area (VTA) were detected in behaviorally impaired MRL-lpr mice, but not in age-matched controls. Reduced brain mass and increased levels of TNF-α in their cerebrospinal fluid (CSF) suggested cerebral atrophy and inflammation. In addition, CSF was neurotoxic to a dopaminergic progenitor cell line. Immunosuppression attenuated CSF cytotoxicity, TNF-α levels, and midbrain neurodegeneration. Supportive of the notion that dying neurons were dopaminergic, the SN of autoimmune mice showed approximately a 35% reduction in the number of TH-positive cells. A three-fold increase in serum brain-reactive antibodies accompanied this loss. Although the source of toxic mediator(s) remains unknown, present results are consistent with the hypothesis that autoimmunity-induced destruction of mesonigral and mesolimbic dopaminergic pathways contributes to the etiology of aberrant behavior in an animal model of neuropsychiatric lupus.

Interleukin-6 and tumor necrosis factor-α levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic–ischemic encephalopathy

ObjectivesTo determine plasma and cerebrospinal fluid (CSF) levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in hypoxic–ischemic encephalopathy (HIE). Study designA controlled, prospective study of 20 control neonates, 19 term newborn infants presenting with sepsis and no meningitis, and 19 asphyxiated term newborn infants. Blood and CSF samples were collected within 48 hours of birth for IL-6 and TNF-α determinations. ResultsMedian plasma IL-6 was similar in sepsis and asphyxia but significantly higher than in control neonates. Median plasma TNF-α was similar in asphyxia and control neonates but significantly lower than in sepsis. In asphyxiated newborn infants, median CSF IL-6 and TNF-α were significantly higher than in sepsis and control neonates. Median CSF IL-6 was significantly higher in sepsis than in control neonates. Median CSF TNF-α was similar in newborn infants with sepsis and control neonates. IL-6 and TNF-α CSF/plasma ratios were similar in newborn infants with sepsis and control neonates but lower than in asphyxiated newborn infants. ConclusionsTerm newborn infants with HIE have elevated CSF IL-6 and TNF-α levels. Plasma IL-6 is increased in asphyxia and sepsis. Plasma TNF-α is increased only in sepsis. High IL-6 and TNF-α CSF/plasma ratios in asphyxia suggest that these cytokines are produced in the brain of term newborn infants with HIE.

New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF)

Five new markers (tumor necrosis factor TNF-α, interleukin IL-1β, IL-6, IL-8, lipopolysaccharide binding protein (LBP)) and 11 old classical markers were evaluated in 180 cerebrospinal fluid (CSF) and serum pairs to discriminate acute bacterial meningitis (BM) on admission from aseptic (viral) meningitis (AM), bacterial meningitis treated with antibiotics (TM) from AM, and AM from multiple sclerosis (MS). Statistical tests were computed which classified correctly ≥90% of the patients with BM, TM, AM at a sum minimum of false positive plus false negative results, and which reached additionally ≥90% sensitivity and specificity. To discriminate BM from AM, CSF IL-6 test ≥500 ng/l and CSF IL-1β test ≥8 ng/l besides CSF lactate test ≥3.5 mmol/l and CSF granulocyte test ≥150 M/l were revealed. CSF lactate test ≥3.2 mmol/l discriminated TM from AM. CSF leukocyte test ≥35 M/l discriminated AM from MS. Tests with the new markers were more laborious, expensive, and time consuming compared to CSF lactate test. Test candidates, detecting ≥80% of patients with ≥80% sensitivity and specificity, were evaluated with CSF TNF-α, IL-8 and LBP, serum IL-6, CSF leukocytes, lymphocytes and monocytes, Qglucose, CSF total protein, albumin, and Qalbumin. All tests should be reviewed in context of clinical findings to diagnose BM reliably.

Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-α in relation to brain edema and contusion following controlled cortical impact injury in rats

Traumatic brain injury is associated with release of the excitotoxin glutamate and production of pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α). Following controlled cortical impact injury, cerebrospinal fluid (CSF) glutamate, IL-6, and TNF-α concentrations were measured to investigate their relationship to evolving tissue damage. Compared to non-traumatized rats CSF glutamate, IL-6 and TNF-α levels were significantly increased by 8 h after trauma ( P<0.005). Parallel to increasing brain swelling and contusion CSF glutamate was significantly elevated over time, reaching highest levels by 48 h (33±4 μM) while IL-6 and TNF-α showed maximum values at 24 h after trauma (42±7 and 4.7±1 pg/ml) ( P<0.005). The observed different temporal profile of CSF glutamate, IL-6, and TNF-α following focal traumatic brain injury could be of therapeutic importance.

Inhibition of leukocyte entry into the brain by the selectin blocker fucoidin decreases interleukin-1 (IL-1) levels but increases IL-8 levels in cerebrospinal fluid during experimental pneumococcal meningitis in rabbits.

The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte recruitment into the cerebrospinal fluid (CSF) during experimental pneumococcal meningitis. In the present study, the effect of fucoidin treatment on the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8 into the CSF was investigated. Rabbits (n = 7) were treated intravenously with 10 mg of fucoidin/kg of body weight every second hour starting 4 h after intracisternal inoculation of approximately 10(6) CFU of Streptococcus pneumoniae type 3 (untreated control group, n = 7). CSF samples were obtained every second hour during a 16-h study period. Treatment with fucoidin caused a consistent and significant decrease in CSF IL-1 levels (in picograms per milliliter) between 12 and 16 h (0 versus 170, 0 versus 526, and 60 versus 1,467, respectively; P < 0.02). A less consistent decrease in CSF TNF-alpha levels was observed in the fucoidin-treated group, but with no significant difference between the two groups (P > 0.05). In contrast, there was no attenuation in CSF IL-8 levels. Indeed, there was a significant increase in CSF IL-8 levels (in picograms per milliliter) in the fucoidin-treated group at 10 and 12 h (921 versus 574 and 1,397 versus 569, respectively; P < 0.09). In conclusion, our results suggest that blood-derived leukocytes mainly are responsible for the release of IL-1 and to some degree TNF-alpha into the CSF during pneumococcal meningitis, whereas IL-8 may be produced by local cells within the brain.

Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis.

The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) were significantly (P < 0.04) upregulated, compared to the beta-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-alpha in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0. 001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P < 0.02) and TNF-alpha (P < 0.02) levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.

Effects of polysaccharide fucoidin on cerebrospinal fluid interleukin-1 and tumor necrosis factor alpha in pneumococcal meningitis in the rabbit.

The inflammatory response in bacterial meningitis is mediated by cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1), which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia. The recruitment of leukocytes into the cerebrospinal fluid (CSF) has been shown to contribute to the neurological damage in this disease, a process which could be enhanced by treatment with antibiotics. In this study, we have used a rabbit meningitis model for two sets of experiments with intracisternal (i.c.) injections of Streptococcus pneumoniae. First, pneumococcal cell wall (PCW) components were injected i.c., inducing an inflammatory response with pleocytosis and increased levels of CSF TNF-alpha) and IL-1 at 6 and 12 h after PCW injection. Treatment with fucoidin, known to inhibit leukocyte rolling, abolished pleocytosis and inhibited the release of TNF-alpha and IL-1. In the second experiment, live pneumococcal bacteria were injected i.c. and treatment with one dose of ampicillin (40 mg/kg of body weight intravenously) was given 16 h after induction of meningitis, causing a sevenfold increase in CSF leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high but did not increase further at 20 h. Also, CSF TNF-alpha levels were high at 16 h and tended to increase at 20 h. Fucoidin treatment prevented the antibiotic-induced increase of CSF leukocytes but had no effect on the TNF-alpha and IL-1 levels. Taken together, fucoidin reduced CSF TNF-alpha and IL-1 levels in acute bacterial meningitis induced by PCW fragments but had no effect later in the course of the disease, when live bacteria were used and an inflammatory increase was caused by a dose of antibiotics.

Cerebrospinal Fluid Levels of Neopterin in Child Patients with Neurological Diseases-In Correlation with IFN-γ or TNF-α

Cerebrospinal fluid (CSF) neopterin levels were measured in child patients with neurological diseases. CSF neopterin levels on admission were significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or in those with non-pleocytotic CSF. CSF neopterin levels in patients with bacterial meningitis one day after admission were higher than those on admission and were markedly elevated with high levels of CSF IFN-γ and TNF-α. CSF neopterin levels in patients with bacterial meningitis one day after admission were related to the period of positive serum C-reactive protein. In patients with non-pleocytotic CSF, CSF neopterin and CSF IFN-y levels were higher in patients with febrile convulsion (FC) than in those with pyrexia only or convulsion (including epilepsy) only. These results suggest that elevation of CSF neopterin in bacterial meningitis results from monocytes/ macrophages costimulated with IFN-γ and TNF-α and that immunological activation in the central nervous system is one of the mechanisms of onset with FC.

Predictive value of plasma and cerebrospinal fluid tumour necrosis factor-α and interleukin-1β concentrations on outcome of full term infants with hypoxic–ischaemic encephalopathy

AIMTo determine the predictive value of plasma and cerebrospinal fluid (CSF) tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations on the outcome of hypoxic–ischaemic encephalopathy (HIE) in full term infants.METHODSThirty...

Are elevated cerebrospinal fluid levels of IL‐6 in sudden unexplained deaths, infectious deaths and deaths due to heart/lung disease in infants and children due to hypoxia?

Many SIDS cases probably die after periods of hypoxia and it has been shown that hypoxia may stimulate IL‐6 production. The purpose of this paper was to examine if there were any correlations between hypoxanthine in vitreous humour and II‐6 in CSF. The concentration of IL‐6, IL‐1β and TNFα in cerebrospinal fluid of 50 Sudden Infant Death syndrome (SIDS) cases, 9 borderline SIDS cases, 18 infectious deaths, 8 violent deaths and 22 cases with heart/lung disease were measured by ELISA. The hypoxanthine (Hx) vitreous humour concentrations in the same groups were determined by high performance liquid chromatography. The IL‐6 levels in cases of infectious death, heart/lung disease and borderline cases were significantly higher than in the SIDS cases (p &lt; 0:01). The Hx levels were in the same range in cases of SIDS, borderline SIDS and infectious death, and they were significantly higher than the levels in cases of violent death and heart/lung disease (p &lt; 0:01). There was no correlation between hypoxanthine and IL‐6 in any of the groups. In the cases studied IL‐6 elevation is probably not induced by hypoxia, but is rather a result of immunological stimulation.

Tumor necrosis factor-α and total parenteral nutrition-induced anorexia

We hypothesize that total parenteral nutrition (TPN) induces anorexia by an increase in anorexigenic cytokines (factors with central action via the hypothalamus) and tested this hypothesis by measuring changes in food intake and cytokines in response to TPN. Fischer rats with an internal jugular catheter and ad libitum food received saline solution for 10 days. On day 11, rats were randomized to TPN (G:F:AA = 50:30:20) for 4 days (days 11 through 14); control rats received on saline solution for 5 days. On day 14, one half of the TPN group was switched back to saline solution for 1 day. Daily food intake was measured. On day 14 in one half of all rats and on day 15 in the remaining, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 alpha were measured in plasma and cerebrospinal fluid (CSF). Spontaneous in vitro TNF-alpha and IL-1 alpha were also measured in peripheral blood mononuclear cells. With TPN, an 80% decrease (p < 0.01) in food intake occurred; plasma TNF-alpha increased (78 +/- 9 pg/ml vs undetectable; p < 0.001), and IL-1 alpha was undetectable. Spontaneous in vitro TNF-alpha and IL-1 alpha production were unchanged. Stoppage of TPN led to return toward normal of food intake and plasma TNF-alpha. TNF-alpha and IL-1 alpha in CSF were undetectable in both groups during and after TPN. Increase in plasma TNF-alpha with no increase in CSF-TNF-alpha during TPN, when food intake decreased, suggests an association between TPN and TNF-alpha but not necessarily cause and effect.

Alterations of anorectic cytokine levels from plasma and cerebrospinal fluid in idiopathic senile anorexia

Plasma and cerebrospinal fluid (CSF) concentrations of two well-known satiety cytokine peptides have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF levels of tumor necrosis factor alfa (TNFα) and interleukin-1β (IL-1β) were assayed by commercially available kits. Elderly under-weight anorectic patients ancd significantly lower levels of TNFα but unchanged concentrations of IL-1β in both plasma and CSF when compared to controls. In addition to significantly lower levels of TNFα in CSF, we found a positive correlaton between the body mass index and CSF TNFα concentrations ( r = 0.61, P < 0.05) in the anorectic group. CSF IL-1β concentrations showed a significant negative correlaton with plasma albumin levels in senile anorectics ( r = −0.66, P < 0.05) but not in controls. On the basis of our findings, we conclude that a decrease in plasma and CSF TNFα concentrations could have beneficial effects for the primary anorexia of aging both at central level to offset anorexia and at peripheral sites decreasing tissue catabolism.

Evaluation of IL-2, sIL2R, IL-6, TNF-α, and IL-1β levels in serum and CSF of patients with optic neuritis

Optic neuritis (ON) is characterized by immune-mediated demyelination of the optic nerve. In this study we addressed the question of cytokine signalling as part of activation of the immune system. 20 patients with first episode of acute idiopathic unilateral ON, prolonged visual evoked potentials, but normal 1.5 tesla MRI of the brain, and normal somatosensory evoked potentials were included into the study. Paired cerebrospinal fluid (CSF) and serum samples of these patients were analyzed for the presence of interleukin (IL-)-2, soluble IL-2R (sIL2R), IL-6, tumor necrosis factor (TNF)-α, and IL-1β by an enzyme-linked immunosorbent assay (IL-2, sIL2R, TNF-α, IL-1β) or a bioassay (IL-6). IL-2 was significantly elevated in the CSF ( P < 0.01), whereas sIL2R ( P < 0.01) and IL-6 ( P < 0.01) were significantly increased in serum. TNF-α could not be detected in CSF or serum, and IL-1β was negative in serum in all but one sample and positive in only low amount (mean 9 pg/ml) in the CSF of 6 20 patients. This cytokine pattern in ON indicates an activation of the immune system within and outside the central nervous system with a predominance of T-cell activation.