TNFMedicine

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-mediated neurotoxicity.

Editor's Note: U.S. patent 6,419,934, issued to Edward Tobinick on July 16, 2002, details the use of biologic anti-TNF therapeutics for HIV-associated neurological conditions.
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-mediated neurotoxicity.
Author(s) Buscemi L, Ramonet D, Geiger JD
Institution Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USA.
Source Neurobiol Dis 2007 Mar 20.
Abstract HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat(1-72) and a mutant Tat(1-72) lacking the neurotoxic epitope (Tat(Delta31-61)) concentration-dependently and markedly increased TNF-alpha production in macrophage-like differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat(1-72) was but Tat(Delta31-61) was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat(1-72) or Tat(Delta31-61) were neurotoxic and their immunoneutralization with an anti-TNF-alpha antibody decreased Tat(1-72)- and Tat(Delta31-61)-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat(1-72) is different from the epitope that is indirectly neurotoxic following production of TNF-alpha from immune cells, and suggest that therapeutic interventions against TNF-alpha might be beneficial against HIV-1 associated neurological disorders.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 17451964

Depressive Symptoms, TNF-alpha, omega-6:omega-3 Fatty Acids, and Inflammation in Older Adults.

Kiecolt-Glaser JK, Belury MA, Porter K, Beversdorf DQ, Lemeshow S, Glaser R
Depressive Symptoms, omega-6:omega-3 Fatty Acids, and Inflammation in Older Adults. Psychosom Med 2007 Mar 30.

Objective: To address how interactions between polyunsaturated fatty acid (PUFA) levels and depressive symptoms were related to proinflammatory cytokine synthesis. Depression and stress promote proinflammatory cytokine production. Dietary intakes of omega-3 (n-3) and omega-6 (n-6) PUFAs also influence inflammation; high n-6:n-3 ratios enhance proinflammatory cytokine production, although n-3 has anti-inflammatory properties.
Methods: Blood samples from 43 older adults (mean age = 66.67 years, SD = 10.09) provided data on PUFAs and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-6 soluble receptor (sIL-6r). Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale.
Results: Depressive symptoms and n-6:n-3 ratios worked together to enhance proinflammatory cytokines beyond the contribution provided by either variable alone, with substantial variance explained by their interaction: 13% for IL-6 and 31% for TNF-alpha, whereas full models accounted for 18% and 40%, respectively. Although predicted cytokine levels were consistent across n-6:n-3 ratios with low depressive symptoms, higher n-6:n-3 ratios were associated with progressively elevated TNF-alpha and IL-6 levels as depressive symptoms increased. Higher levels of sIL-6r were associated with higher n-6:n-3 ratios. Six individuals who met the criteria for major depressive disorder had higher n-6:n-3 ratios and TNF-alpha, IL-6, and sIL-6r levels than those who did not meet the criteria; excluding these six individuals reduced the variance explained by the depressive symptoms and n-6:n-3 ratio interaction.
Conclusions: Diets with high n-6:n-3 PUFA ratios may enhance the risk for both depression and inflammatory diseases.

Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study.

Farbu E, Rekand T, Vik-Mo E, Lygren H, Gilhus NE, Aarli JA
Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study. [JOURNAL ARTICLE]
Eur J Neurol 2007 Jan; 14(1) :60-65.

Post-polio syndrome (PPS) is characterized by new muscle weakness, atrophy, fatigue and pain developing several years after the acute polio. Some studies suggest an ongoing inflammation in the spinal cord in these patients. From this perspective, intravenous immunoglobulin (IvIg) could be a therapeutic option. We performed a double-blinded randomized controlled pilot study with 20 patients to investigate the possible clinical effects of IvIg in PPS. Twenty patients were randomized to either IvIg 2 g/kg body weight or placebo. Primary endpoints were changes in pain, fatigue and muscle strength 3 months after treatment. Surrogate endpoints were changes in cerebrospinal fluid (CSF) cytokine levels. Secondary endpoints were pain, fatigue and isometric muscle strength after 6 months. Patients receiving IvIg reported a significant improvement in pain during the first 3 months, but no change was noted for subjective fatigue and muscle strength. CSF levels of tumour necrosis factor-alpha (TNF-alpha) were increased compared with patients with non-inflammatory neurological disorders. In conclusion, in this small pilot study no effect was seen with IvIg treatment on muscle strength and fatigue, however IvIg treated PPS patients reported significantly less pain 3 months after treatment. TNF-alpha was increased in the CSF from PPS patients. The results are promising, but not conclusive because of the low number of patients studied.

TNF-alpha in post-polio syndrome

Gonzalez H, Khademi M, Andersson M, Wallström E, Borg K, Olsson T
Prior poliomyelitis-evidence of cytokine production in the central nervous system.
J Neurol Sci 2002 Dec 15; 205(1) :9-13.

In order to study the role of a possible inflammatory reaction in the post-polio syndrome (PPS) four key cytokines were determined by means of mRNA expression in mononuclear cells from cerebrospinal fluid (CSF) and peripheral blood of 13 patients. Data were compared with those of samples from eight non-inflammatory control persons.The PPS-patients displayed increased numbers of CSF cells expressing mRNA for TNF-alpha (p<0.02), IFN-gamma (p<0.02), IL-4 (p<0.001) and IL-10 (p<0.05), in comparison to the non-inflammatory controls.As positive controls, samples from patients with Multiple Sclerosis (MS) were examined.We conclude that there is a chronic intra CNS expression of inflammatory cytokines in PPS, in the range of that in MS, a well known neuroinflammatory disease. However, the pathogenic significance of this is unclear.

Spinal and Supraspinal Changes in Tumor Necrosis Factor-alpha Expression Following Excitotoxic Spinal Cord Injury.

J Mol Neurosci. 2007;31(1):13-22.
Spinal and Supraspinal Changes in Tumor Necrosis Factor-alpha Expression Following Excitotoxic Spinal Cord Injury.

Brewer KL,
Nolan TA.
Department of Emergency Medicine, PCMH 3ED304, East Carolina University Brody School of Medicine, Greenville NC 27834.
The role of tumor necrosis factor-alpha (TNF-alpha) after spinal cord injury (SCI) is well characterized in the cord, but the impact of this inflammatory process on supraspinal levels is unknown. This study examines TNF-alpha mRNA and protein levels in the brains and spinal cords of mice after SCI. Mice received intraspinal injections of quisqualic acid (QUIS) to create an excitotoxic injury that is known to result in pain behaviors. An ELISA determined serum levels of TNF-alpha, whereas real-time PCR and Western blot analysis were used to determine mRNAand protein levels, respectively, at 3, 6, 12, 24, 48, 72 h, or 14 d postinjury. No difference existed in serum TNF-alpha levels between sham- and QUIS-injected animals. TNF-alpha mRNA in the cord was increased at 3, 6, 12, and 24 h in QUIS-injected animals relative to shams. TNF-alpha protein was elevated at 12 and 48 h postinjury. TNF-alpha mRNAlevels in the brain were elevated at 12 and 24 h, with elevated protein levels at 6 h. Animals that developed pain behaviors had increased levels of TNF-alpha mRNA in the brain. Excitotoxic SCI results in altered TNF-alpha mRNA and protein levels in the cords and brains of mice within 6 h of injury. These changes likely contribute to the pathogenesis of injury within the cord. The role of TNF-alpha in the brain postinjury has not been defined but might contribute to the development of pain post-SCI.
PMID: 17416966 [PubMed - in process]

Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.

This new article from the Department of Neurology at Boston University constitutes another piece of scientific evidence which supports the concept of excess TNF-alpha as a therapeutic target for the treatment of dementia, including both Alzheimer's Disease and vascular dementia [Editor's comment].

Title Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.
Author(s) Jefferson AL, Massaro JM, Wolf PA, Seshadri S, Au R, Vasan RS, Larson MG, Meigs JB, Keaney JF, Lipinska I, Kathiresan S, Benjamin EJ, DeCarli C
Institution Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA. angelaj@bu.edu
Source Neurology 2007 Mar 27; 68(13) :1032-8.
Abstract BACKGROUND: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]).
METHODS: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.
RESULTS: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.
CONCLUSIONS: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.
Language eng
Pub Type(s) Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PubMed ID 17389308