Interleukin-10 and Tumor Necrosis Factor-α Gene Polymorphisms in Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease in humans killing nearly three million people and eight million cases annually. The cytokines TNF-α and IL-10 have been implicated in the pathogenesis of TB. Certain single nucleotide polymorphisms within the promoter region of the IL10 and TNF genes have been associated with altered levels of circulating IL10 and TNF- α. We analyzed TNF-α (−308 G/A, −238 G/A, −376 G/A) and IL10 (−1,082 G/A, −819 C/T, −592 C/A) polymorphisms in 128 patients with TB and 80 healthy subjects using by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). A significant association was found between TB and −1,082 G allele (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41). Significant difference was observed in IL10 GCC and ACC haplotypes distribution between TB and control subjects (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41; Pc: 0.004, O.R 0.53, 95% CI 0.35–0.81). No statistically significant association was found between IL-10 −819 C/T, TNF-α 308 G/A, −238 G/A, −376 G/A polymorphisms, functional TNFα/IL-10 genotypes and TB. Our findings suggest that IL-10 108 2G/A alleles or haplotypes containing these alleles may influence the Th1/Th2 balance and hence may play a role in TB susceptibility and increase risk of developing disease. This polymorphism may be one of the many genetic factors affecting disease outcome.     

Expression of Tumor Necrosis Factor-α and Transforming Growth Factor-β1 in Acute Liver Injury

Abstract

Tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) have a number of in vitro functions that could be important in vivo in acute liver injury and repair. Therefore, we investigated these two cytokines in acute liver damage. Northern blots of RNA isolated from rats sacrificed at various time intervals after a single oral dose of CCl₄ revealed that TNF-α mRNA levels were elevated within 6 hr of CCl₄ administration and returned to control values by 24–32 hr. In contrast, TGF-β1 mRNA levels started to rise significantly at 24 hr, peaked at 48 hr, and approached baseline levels by 72 hr. Identical changes in TNF-α and TGF-β1 mRNA levels were also seen with D-galactosamine-induced hepatotoxicity. Immunohistochemical analysis using a TGF-β1 antibody demonstrated increased hepatic staining in CCl₄-treated rats, at times corresponding to the increases in TGF-β1 gene expression. Therefore, there is a differential expression of these cytokines in acute CCl₄ and galactosamine hepatotoxicity with an early rise in TNF-α, suggesting that this cytokine may affect inflammation and cell toxicity, while TGF-β1 peaks later, when it may regulate hepatocyte proliferation and extracellular matrix repair.     

The Pulmonary Inflammatory Response to Experimental Fecal Peritonitis: Relative Roles of Tumor Necrosis Factor-α and Endotoxin

The roles of endotoxin (LPS) and tumor necrosis factor- (TNF-) in the causation of organ injury during sepsis are unclear. To study LPS and TNF- in the genesis of lung inflammation after cecal ligation and puncture (CLP), we used endotoxin-resistant (C3H/HeJ) and endotoxin-sensitive mice (C3H/HeOuJ). We examined lung neutrophil sequestration, interleukin 1 (IL-1) mRNA expression, IL-1 protein expression, and injury. We also determined the expression of two C-X-C chemokine mRNAs, macrophage inflammatory protein-2 (MIP-2) and KC, in the lung to determine whether in vivo, endotoxin, or TNF- are significant modulators of MIP-2 and KC mRNA expression. After CLP, increased neutrophils sequestrated in the lungs of both strains of mice and coincided with an increase in expression of IL-1, MIP-2 and KC mRNAs, and IL-1 protein. Lung and serum TNF- were significantly increased in the C3H/HeOuJ strain but not in the C3H/HeJ strain. Histologic studies of the lung revealed similar injury in both strains. Our results suggest that bacterial factors other than endotoxin cause lung neutrophil sequestration and injury after CLP and further, that TNF- production is not a prerequisite. Our findings also suggest a potential role for local pulmonary chemokine production in the control of neutrophil sequestration after CLP.     

Signaling Pathways for Fcγ Receptor-Stimulated Tumor Necrosis Factor-α Secretion and Respiratory Burst in RAW 264.7 Macrophages

Fc gamma receptor (Fc gammaR) signaling mediates several important macrophage functions including cytokine secretion and respiratory burst. The present study describes the development of a model using the macrophage cell line, RAW 264.7 for studying Fc gammaR-stimulated tumor necrosis factor-alpha (TNF-alpha) secretion and hydrogen peroxide (H2O2) production. In unprimed cells these functions were low but pretreatment with interferon-gamma augmented Fc gammaR-stimulated TNF-alpha secretion and H2O2 production to levels that were about half that caused by lipopolysaccharide (LPS) and zymosan, respectively. Studies on the signaling pathways found that TNF-alpha secretion stimulated by either Fc gammaR or LPS was decreased by inhibitors of PKC, MAPK p42/p44, and MAPK p38. TNF-alpha secretion was also reduced by the combination of PLC and PLD inhibitors but not by the individual inhibitors alone. H2O2 production stimulated by either Fc gammaR or zymosan was blocked by inhibitors of PKC, PLC, PLD, and MAPK p42/44 but not by MAPK p38. Thus, interferon-gamma treated RAW 264.7 cells are a model of inflammatory macrophages and are well suited for further study of these signaling pathways.     

Polymorphism of Promotor Region of the Tumor Necrosis Factor-α Gene in Patients with Viral Hepatitis C

Study of the pathogenesis of viral hepatitis C is of primary importance because of persistence of this virus and high incidence of chronic course of this disease, and as a consequence, development of cirrhotic and neoplastic processes in the liver determining high mortality from this condition. Proinflammatory cytokines, in particular, tumor necrosis factor, play an important role in the development of these pathological processes. The content of tumor necrosis factor in the circulating blood plasma and hepatocytes increases in acute and chronic hepatitis C. It seems that the capacity of cells to produce proinflammatory IL in high or low levels spontaneously or after antigenic stimulation largely determines the outcome of infectious process in contact with the virus.     

The Risk of Tuberculosis in Korean Patients with Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-α Blockers

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-α blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-α blocker naïve and 160 TNF-α blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-α blocker users, and 0.45 for TNF-α-blocker-naïve patients. The adjusted risk ratio of TB in IBD patients receiving TNF-α blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-α blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-α blockers. Treatment with TNF-α blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-α blocker therapy.

Graphical Abstract

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High-Carbohydrate Diet Selectively Induces Tumor Necrosis Factor-α Production in Mice Liver

Obesity may represent a state of chronic low-grade inflammation associated with infiltration of adipose tissue by inflammatory cells. Tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1/JE), two important inflammatory cytokines, have been shown to be regulated according to changes in body adiposity. In this study on Swiss mice, we compared the influences of long-term high-carbohydrate (HC) or high-fat (HF) diet on adiposity, glucose tolerance, and secretion of TNF-α and MCP-1/JE by adipose tissue and liver. For 8 weeks, male Swiss mice (7–8 weeks) were fed either standard laboratory rodent diet (control group), HC diet (64% carbohydrate, 19% protein, and 11% fat), or HF diet (45% carbohydrate, 17% protein, and 38% fat), with the latter two diets having no fiber. Oral glucose tolerance test, triacylglycerol (TAG) plasma concentration, and systemic or tissue levels of the two proinflammatory cytokines were determined. Body weight increased by approximately 20% in mice fed the experimental diets compared with mice fed the control diet. Systemically, the hypercaloric diets induced hyperglycemia with impairment in glucose tolerance, elevated circulating TAG levels, and increased plasma concentrations of TNF-α and MCP-1/JE. In the target organs (adipose tissue and liver), both diets increased MCP-1/JE levels. However, the HC diet, but not the HF diet, was able to increase TNF-α concentration in the liver. These results have shown that the nature of nutrients influences the type of proinflammatory cytokines in target organs and may contribute to the comorbidities of obesity.     

Kinetics of Receptor-Mediated Uptake and Processing of Interferon-α2a and Tumor Necrosis Factor-α by Human Tumor Cells

Abstract

The kinetics of uptake and processing of recombinant human interferon-a₂a (IFN) and recombinant human tumor necrosis factor-a (TNF) were studied in human epithelial rumor cell lines differing in sensitivity to growth inhibition by IFN and TNF. Concentrations of [¹²⁵I]IFN or [¹²⁵I]TNF at the cell surface and internalized by confluent cell monolayers incubated at 37°C were measured as a function of time. Cells incubated with [¹²⁵I]IFN exhibited transient maxima of surface-associated and internalized [^I25I]IFN after 1-2 hr of incubation followed by a steady-state attained after approximately 6 hr of exposure to [¹²⁵I]IFN. Concentration of [¹²⁵I]TNF associated with the plasma membrane displayed a maximum within 20 min of incubation. Internalized radioactivity increased with time and did not achieve a steady state. We analyzed the time-dependent concentrations of membrane-associated and internalized cytokines by use of a compartmental model. This model describes changes in concentrations of free surface receptors, of ligand-receptor complex at the membrane and of internalized ligand and contains a term for receptor recycling. The rate constants for concentration changes were evaluated by fitting model functions to data. The best fits for IFN were obtained without receptor recycling. The best-fit values for the endo-cytotic rate constant (k_tlFN) varied among cell lines from 2.4x10^?4 to 7.8 x10^?4 sec^?1. To obtain fits to time-dependent concentrations of surface-associated and internalized [¹²⁵I]TNF, introduction of a term for receptor recycling was required. Best-fit values for k, _TNF ranged among cell lines from 8.4x10^?4 to 2.5x10^?3 sec^?1. For every cell line, the value of k_lTNF was larger than the value of k_clFN. We tested the significance of these differences by substituting K.IFN ^tor K.TNT ^as fixed parameters in fits to data for TNF and v.v., respectively. Under these conditions, fits were significantly worse. Our data indicate that recycling is insignificant in kinetics of Type-I IFN receptor; recycling is necessary to explain the kinetics of TNF receptor. Upon binding, TNF is taken up by cells faster than IFN and is eliminated from cells more slowly than IFN.     

IFN-γ Inhibits the Suppressive Effects of PGE2 on the Production of Tumor Necrosis Factor-α by Mouse Macrophages

Tumor necrosis factor-α (TNF-α) has become known as a central mediator of responses to endotoxin, rheumatoid diseases, and other forms of inflammation. Current investigations indicate that the production of TNF-α is controlled by other mediators, including interferon-γ (IFN-γ) and prostaglandin E₂ (PGE₂). In the present study, we investigated the regulatory effects of IFN-γ and/or PGE₂ on LPS-induced TNF-α production and mRNA expression in mouse peritoneal macrophages using the enzyme immunoassay and Northern blot analysis, respectively. In response to 10 ng/ml of LPS, TNF-α production reached a maximum at approximately 4 hrs, followed by rapid decline. At the molecular level, TNF-α mRNA accumulated rapidly after LPS exposure, reaching a peak by 3 hr, and declined more rapidly than did the production of TNF-α. Exposure of macrophages to 100 U/ml of IFN-γ caused an increase in both the TNF-α production and mRNA expression induced by LPS. Exogenous PGE₂ caused a dose dependent reduction in LPS-induced TNF-α mRNA accumulation as well as TNF-α production. Macrophages primed with IFN-γ showed the reduced responsiveness to the suppressive effect of PGE₂ on the production of TNF-α and the accumulation of TNF-α mRNA. These findings indicate that the suppressive effects induced by PGE₂ on the accumulation of TNF-α mRNA as well as the production of TNF-α can be reduced by the pretreatment of macrophages with IFN-γ. These studies demonstrate the role of IFN-γ as an immunomodulating compound that may effectively regulate TNF-α production by modulation of macrophage responsiveness to PGE₂.     

Effects of Isoflavones and Soybeans Fermented with Bacillus subtilis on Lipopolysaccharide-Induced Production of Tumor Necrosis Factor-α and Fibrinolysis In Vivo

The effects of isoflavones and of a derivative of soybeans fermented with Bacillus subtilis, designated Nattoesse?, on the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-α (TNF-α) and fibrinolysis were investigated in vivo. The dietary supplement Nattoesse? contains several isoflavones. Therefore, we examined the effects of individual isoflavones (daidzein, daidzin, genistein, and genistin) on the LPS-induced production of TNF-α. Intraperitoneal injections of daidzein, daidzin, and genistin (but not of genistein before a challenge with LPS) resulted in significant depression of serum levels of TNF-α in mice. Daidzein had the strongest activity in this assay. Oral administration of daidzein to mice also had a significant suppressive effect, as compared with that of the Citrus flavanone naringin. In galactosamine-sensitized mice, by contrast, the suppression of LPS-induced lethal shock by daidzein was very weak. Nattoesse? did not inhibit the production of TNF-α nor did it prevent lethal shock. However, oral administration of Nattoesse? to mice significantly suppressed LPS-induced increases in scores of the fibrin degradation product, and the effect was both dose- and time-dependent. Thus, it appears that Nattoesse? has fibrinolytic activity during LPS-induced circulatory failure.     

Tumor Necrosis Factor-α Up-Regulates the Expression of β1,4-Galactosyltransferase-I in Human Fibroblast-like Synoviocytes

β1,4-Galactosyltransferase-I (β1,4-GalT-I), which transfers galactose to the terminal N-acetylglucosamine of N- and O-linked glycans in a β1,4-linkage, is considered to be the major galactosyltransferase among the seven members of the subfamily responsible for β4 galactosylation. We previously reported, for the first time, that β1,4-GalT-I may play an important role in the inflammatory processes in synovial tissue of patients with rheumatoid arthritis (RA). In this study, we analyzed whether β1,4-GalT-I expression correlates with the expression of tumor necrosis factor-α (TNF-α) in RA. We show firstly the overexpression and co-localization of β1,4-GalT-I and TNF-α in synovial tissue of RA patients. Then, lipopolysaccharide (LPS) induces β1,4-GalT-I mRNA up-regulation in fibroblast-like synoviocytes (FLSs) through endogenous TNF-α overexpression. In addition, we observed that not only endogenous TNF-α but also exogenous TNF-α induced β1,4-GalT-I mRNA production in FLSs, and TNF-α-knockdown reverses the up-regulation of β1,4-GalT-I in FLSs induced by LPS or TNF-α. These results suggest that TNF-α contributes to the up-regulation of β1,4-GalT-I mRNA in human FLSs.     

Lipopolysaccharide-Induced Upregulation of Tumor Necrosis Factor-α (TNF-α) in Rat Spinal Cord

The proinflammatory and lipopolysaccharide (LPS)-inducible cytokine tumor necrosis factor α (TNF-α) has been shown to enhance primary sensory nociceptive signaling. However, the precise cellular sites of TNF-α synthesis is still a matter of controversy. Therefore, we focused our study on TNF-α protein synthesis and expression patterns in spinal cord of controls and rats under systemic challenge with LPS. The Enzyme-linked immunosorbent (ELISA) assay showed that the protein level of TNF-α reached peak at 6 h. Double immunofluorescence revealed that LPS-induced expression of TNF-α exclusively located in a subpopulation of neurons, microglia and macrophages. These observations have demonstrated the production of this proinflammatory cytokine by spinal neurons, but the inherent mechanisms remain unknown. Further studies are needed to confirm the pathogenic role of tumor necrosis factor in the early stage of inflammation. Qin Shen and Dan Zhou contributed equally to this work.     

Synergistic Actions of Blocking Angiopoietin-2 and Tumor Necrosis Factor-α in Suppressing Remodeling of Blood Vessels and Lymphatics in Airway Inflammation

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.Remodeling of blood vessels and lymphatics contributes to the pathophysiology of many chronic inflammatory diseases, including asthma, chronic bronchitis, chronic obstructive pulmonary disease, inflammatory bowel disease, and psoriasis.^{1, 2, 3} When inflammation is sustained, capillaries acquire venule-like properties that expand the sites of plasma leakage and leukocyte influx. Consistent with this transformation, the remodeled blood vessels express P-selectin, intercellular adhesion molecule 1 (ICAM-1), EphB4, and other venular markers.^{4, 5, 6} The changes are accompanied by remodeling of pericytes and disruption of pericyte-endothelial crosstalk involved in blood vessel quiescence.⁷ Remodeling of blood vessels is accompanied by plasma leakage, inflammatory cell influx, and sprouting lymphangiogenesis.^{6, 8, 9}Mycoplasma pulmonis infection causes sustained inflammation of the respiratory tract of rodents.¹⁰ This infection has proved useful for dissecting the features and mechanisms of vascular remodeling and lymphangiogenesis.^{6, 9, 10} At 7 days after infection, there is widespread conversion of capillaries into venules, pericyte remodeling, inflammatory cell influx, and lymphatic vessel sprouting in the airways and lung.^{4, 5, 6, 7, 8, 9} Many features of chronic M. pulmonis infection in mice are similar to Mycoplasma pneumoniae infection in humans.¹¹Angiopoietin-2 (Ang2) is a context-dependent antagonist of Tie2 receptors^{12, 13} that is important for prenatal and postnatal remodeling of blood vessels and lymphatic vessels.^{13, 14, 15} Ang2 promotes vascular remodeling,^{4, 5} lymphangiogenesis,^{15, 16, 17} and pericyte loss¹⁸ in disease models in mice. Mice genetically lacking Ang2 have less angiogenesis, lymphangiogenesis, and neutrophil recruitment in inflammatory bowel disease.³ Ang2 has proved useful as a plasma biomarker of endothelial cell activation in acute lung injury, sepsis, hypoxia, and cancer.¹⁹Like Ang2, tumor necrosis factor (TNF)-α is a mediator of remodeling of blood vessels and lymphatics.^{8, 9, 20, 21} TNF triggers many components of the inflammatory response, including up-regulation of expression of vascular cell adhesion molecule-1, ICAM-1, and other endothelial cell adhesion molecules.²² TNF inhibitors reduce inflammation in mouse models of inflammatory disease^{23, 24} and are used clinically in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn''s disease, psoriatic arthritis, and some other inflammatory conditions.^{24, 25} Indicative of the complex role of TNF in disease, inhibition or deletion of TNF can increase the risk of serious infection by bacterial, mycobacterial, fungal, viral, and other opportunistic pathogens.²⁶TNF and Ang2 interact in inflammatory responses. TNF increases Ang2 expression in endothelial cells in a time- and dose-dependent manner, both in blood vessels²⁷ and lymphatics.¹⁶ Administration of TNF with Ang2 increases cell adhesion molecule expression more than TNF alone.^{16, 28} Similarly, Ang2 can promote corneal angiogenesis in the presence of TNF, but not alone.²⁹ In mice that lack Ang2, TNF induces leukocyte rolling but not adherence to the endothelium.²⁸ Ang2 also augments TNF production by macrophages.^{30, 31} Inhibition of Ang2 and TNF together with a bispecific antibody can ameliorate rheumatoid arthritis in a mouse model.³²With this background, we sought to determine whether Ang2 and TNF act together to drive the remodeling of blood vessels and lymphatics in the initial inflammatory response to M. pulmonis infection. In particular, we asked whether Ang2 and TNF have synergistic actions in this setting. The approach was to compare the effects of selective inhibition of Ang2 or TNF, individually or together, and then assess the severity of vascular remodeling, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic sprouting. Functional consequences of genome-wide changes in gene expression were analyzed by Ingenuity Pathway Analysis (IPA)^{33, 34} and the Database for Annotation, Visualization and Integrated Discovery (DAVID).³⁵ The studies revealed that inhibition of Ang2 and TNF together, but not individually, completely prevented the development of vascular remodeling and lymphatic sprouting and had synergistic effects in suppressing gene expression and cellular pathways activated during the initial stage of the inflammatory response.     

Serum-Soluble Receptors for Tumor Necrosis Factor-α and Interleukin-2, and Neopterin in Acute Rheumatic Fever

Immune activation may play an important role in the pathogenesis of acute rheumatic fever (ARF). The objective of the present study was to investigate serum concentrations of various markers of immune activation in ARF patients. Sera of 32 patients with ARF were investigated, 20 of them in follow-up. Radioimmunoassay was used to quantify neopterin and ELISA for the measurement of 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R) and soluble interleukin-2 receptor (sIL2-R). Markers of immune activation were found to be raised in 48% (sTNF-R), 28% (sIL2-R), and 78% (neopterin) of patients at the onset of ARF. There were significant correlations between the concentrations of neopterin and sTNF-R (rs = 0.60, P < 0.001) or sIL2-R (rs = 0.35, P < 0.05). Higher neopterin concentrations were found in patients with combined aortic and mitral insufficiency than in patients with mitral valve lesions alone (U = 2.67, P <0.05) or without valve lesion (U = 2.36, P < 0.05). Increased concentrations of neopterin, sTNF-R, and sIL2-R demonstrate activation of the cellular immune system in patients with ARF. Higher serum neopterin concentrations are associated with development of combined aortic and mitral insufficiency during the first episode of ARF.     

Intracerebral Production of Tumor Necrosis Factor-α, a Local Neuroprotective Agent, in Alzheimer Disease and Vascular Dementia

The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1, IL-6, TNF-, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF- on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF- compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF- and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF--exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF- in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF- exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.     

Low In Vitro Production of Interferon-γ and Tumor Necrosis Factor-α in HIV-Seronegative Patients with Pulmonary Disease Caused by Nontuberculous Mycobacteria

We studied 32 HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria (NTM). Immunologic studies included lymphocyte subset analysis by flow cytometry, measurement of interferon- (IFN-) and tumor necrosis factor- (TNF-) production followingin vitro stimulation of diluted whole blood (DWB) and peripheral blood mononuclear cells (PBMC) by phytohemagglutinin (PHA), anti-CD3 as well as purified protein derivative of tuberculin (PPD), and in four cases with different amounts of the very mycobacterium, which caused disease in these patients. Data were compared to those of 30 HIV-seronegative patients with disease byMycobacterium tuberculosis (MTb). Following -CD3-stimulation of PBMC, NTM patients showed lower IFN-(P < 0.00005) and lower TNF-(P < 0.02). For a subgroup of tuberculin skin test-positive NTM patients we found significantly lower PPD-induced IFN- releases in cultured DWB(P < 0.0002) and PBMC(P < 0.0004) compared to MTb patients. Data for PPD-induced TNF- release for this subgroup were also significant(P < 0.001 andP < 0.05, respectively). The four NTM patients with poor PPD-induced IFN- response hardly showed increased cytokine production on stimulation with their specific mycobacterium. The lower production capacity of IFN- and TNF- of NTM patients compared to the MTb patients points to an immunologic imbalance forming the basis for their increased susceptibility to pulmonary infections by nontuberculous mycobacteria.