Persistent Periodontal Disease Hampers Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis

Objective: This study aimed to evaluate prospectively the influence and the evolution of periodontal disease (PD) in rheumatoid arthritis (RA) patients submitted to anti-tumor necrosis factor (TNF) therapy. Methods: Eighteen patients with RA (according to the American College of Rheumatology criteria) were assessed for PD before (BL) and after 6 months (6M) of anti-TNF treatment: 15 infliximab, 2 adalimumab, and 1 etanercept. Periodontal assessment included plaque and gingival bleeding indices, probing pocket depth, cementoenamel junction, and clinical attachment level. Rheumatologic evaluation was performed blinded to the dentist's assessment: demographic data, clinical manifestations, and disease activity (Disease Activity Score using 28 joints [DAS28], erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]). Results: The median age and disease duration of patients with RA were 50 years (25-71 y) and 94% were female. Periodontal disease was diagnosed in 8 patients (44.4%). Comparing BL to 6M, periodontal parameters in the entire group remained stable (P > 0.05) throughout the study (plaque and gingival bleeding indices, probing pocket depth, cementoenamel junction, and clinical attachment level), whereas an improvement in most analyzed RA parameters was observed in the same period: DAS28 (5.5 vs. 3.9, P = 0.02), ESR (21 vs. 12.5 mm/first hour, P = 0.07), and CRP (7.8 vs. 2.8 mg/dL, P = 0.25). Further analysis revealed that this improvement was restricted to the group of patients without PD (DAS28 [5.5 vs. 3.6, P = 0.04], ESR [23.0 vs. 11.5 mm/first hour, P = 0.008], and CRP [7.4 vs. 2.1, P = 0.01]). In contrast, patients with PD had lack of response, with no significant differences in disease activity parameters between BL and 6M: DAS28 (5.2 vs. 4.4, P = 0.11), ESR (17.0 vs. 21.0, P = 0.56), and CRP (9.0 vs. 8.8, P = 0.55). Conclusions: This study supports the notion that PD may affect TNF blocker efficacy in patients with RA. The possibility that a sustained gingival inflammatory state may hamper treatment response in this disease has high clinical interest because this is a treatable condition.

Metabolic flux analysis for directing metabolism of Streptomyces olindensis from growth to anti-tumor drug (cosmomycin) production

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES, Brazil

Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy?

Abstract Introduction Sclerostin levels have been reported to be low in ankylosing spondylitis (AS), but there is no data regarding the possible role of this Wnt inhibitor during anti-tumor necrosis factor (TNF) therapy. The present study longitudinally evaluated sclerostin levels, inflammatory markers and bone mineral density (BMD) in AS patients under anti-TNF therapy. Methods Thirty active AS patients were assessed at baseline, 6 and 12 months after anti-TNF therapy regarding clinical parameters, inflammatory markers, BMD and baseline radiographic damage (mSASSS). Thirty age- and sex-matched healthy individuals comprised the control group. Patients' sclerostin levels, sclerostin binding low-density lipoprotein receptor-related protein 6 (LRP6) and BMD were evaluated at the same time points and compared to controls. Results At baseline, AS patients had lower sclerostin levels (60.5 ± 32.7 vs. 96.7 ± 52.9 pmol/L, P = 0.002) and comparable sclerostin binding to LRP6 (P = 0.387) than controls. Improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis quality of life (ASQoL) was observed at baseline vs. 6 vs. 12 months (P < 0.01). Concomitantly, a gradual increase in spine BMD (P < 0.001) and a positive correlation between baseline mSASSS and spine BMD was found (r = 0.468, P < 0.01). Inflammatory parameters reduction was observed comparing baseline vs. 6 vs. 12 months (P <0.01). Sclerostin levels progressively increased [baseline (60.5 ± 32.7) vs. 6 months (67.1 ± 31.9) vs. 12 months (72.7 ± 32.3) pmol/L, P <0.001]. At 12 months, the sclerostin levels remained significantly lower in patients compared to controls (72.7 ± 32.3 vs. 96.70 ± 52.85 pmol/L, P = 0.038). Moreover, sclerostin serum levels at 12 months were lower in the 10 patients with high C reactive protein (CRP) (≥ 5 mg/l) compared to the other 20 patients with normal CRP (P = 0.004). Of note, these 10 patients with persistent inflammation also had lower sclerostin serum levels at baseline compared to the other patients (P = 0.023). Univariate logistic regression analysis demonstrated that AS patients with lower sclerostin serum levels had an increased risk to have high CRP at 12 months (odds ratio = 7.43, 95% CI 1.23 to 45.01, P = 0.020) than those with higher sclerostin values. Conclusions Persistent low sclerostin levels may underlie continuous inflammation in AS patients under anti-TNF therapy.

Differential Gene Expression Profiles May Differentiate Responder and Nonresponder Patients with Rheumatoid Arthritis for Methotrexate (MTX) Monotherapy and MTX plus Tumor Necrosis Factor Inhibitor Combined Therapy

Objective. We aimed to evaluate whether the differential gene expression profiles of patients with rheumatoid arthritis (RA) could distinguish responders from nonresponders to methotrexate (MTX) and, in the case of MTX nonresponders, responsiveness to MTX plus anti-tumor necrosis factor-alpha (anti-TNF) combined therapy. Methods. We evaluated 25 patients with RA taking MTX 15-20 mg/week as a monotherapy (8 responders and 17 nonresponders). All MTX nonresponders received intliximab and were reassessed after 20 weeks to evaluate their anti-TNF responsiveness using the European League Against Rheumatism response criteria. A differential gene expression analysis from peripheral blood mononuclear cells was performed in terms of hierarchical gene clustering, and an evaluation of differentially expressed genes was performed using the significance analysis of microarrays program. Results. Hierarchical gene expression clustering discriminated MTX responders from nonresponders, and MTX plus anti-TNF responders from nonresponders. The evaluation of only highly modulated genes (fold change > 1.3 or < 0.7) yielded 5 induced (4 antiapoptotic and CCL4) and 4 repressed (4 proapoptotic) genes in MTX nonresponders compared to responders. In MTX plus anti-TNF nonresponders, the CCL4, CD83, and BCL2A1 genes were induced in relation to responders. Conclusion. Study of the gene expression profiles of RA peripheral blood cells permitted differentiation of responders from nonresponders to MTX and anti-TNF. Several candidate genes in MTX non-responders (CCL4, HTRA2, PRKCD, BCL2A1, CAV1, TNIP1 CASP8AP2, MXD1, and BTG2) and 3 genes in MTX plus anti-TNF nonresponders (CCL4, CD83, and BCL2A1) were identified for further study. (First Release July 1 2012; J Rheumatol 2012;39:1524-32; doi:10.3899/jrheum.120092)

Interleukin-10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth

Abstract Background Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like, induce T cell regulatory phenotype and play an important role in tumor growth. M2 macrophages secrete several cytokines, among them IL-10, which has been shown to play a role in T cell suppression by tumor macrophages in other tumor models. In this work, we sought to establish if IL-10 is part of the mechanism by which HPV tumor associated macrophages induce T cell regulatory phenotype, inhibiting anti-tumor activity and facilitating tumor growth. Results TC-1 tumor cells do not express or respond to IL-10, but recruit leukocytes which, within the tumor environment, produce this cytokine. Using IL-10 deficient mice or blocking IL-10 signaling with neutralizing antibodies, we observed a significant reduction in tumor growth, an increase in tumor infiltration by HPV16 E7 specific CD8 lymphocytes, including a population positive for Granzyme B and Perforin expression, and a decrease in the percentage of HPV specific regulatory T cells in the lymph nodes. Conclusions Our data shows that in the HPV16 TC-1 tumor mouse model, IL-10 produced by tumor macrophages induce regulatory phenotype on T cells, an immune escape mechanism that facilitates tumor growth. Our results point to a possible mechanism behind the epidemiologic data that correlates higher IL-10 expression with risk of cervical cancer development in HPV infected women.

Insights into Phosphate Cooperativity and Influence of Substrate Modifications on Binding and Catalysis of Hexameric Purine Nucleoside Phosphorylases

The hexameric purine nucleoside phosphorylase from Bacillus subtilis (BsPNP233) displays great potential to produce nucleoside analogues in industry and can be exploited in the development of new anti-tumor gene therapies. In order to provide structural basis for enzyme and substrates rational optimization, aiming at those applications, the present work shows a thorough and detailed structural description of the binding mode of substrates and nucleoside analogues to the active site of the hexameric BsPNP233. Here we report the crystal structure of BsPNP233 in the apo form and in complex with 11 ligands, including clinically relevant compounds. The crystal structure of six ligands (adenine, 2'deoxyguanosine, aciclovir, ganciclovir, 8-bromoguanosine, 6-chloroguanosine) in complex with a hexameric PNP are presented for the first time. Our data showed that free bases adopt alternative conformations in the BsPNP233 active site and indicated that binding of the co-substrate (2'deoxy) ribose 1-phosphate might contribute for stabilizing the bases in a favorable orientation for catalysis. The BsPNP233-adenosine complex revealed that a hydrogen bond between the 5' hydroxyl group of adenosine and Arg(43*) side chain contributes for the ribosyl radical to adopt an unusual C3'-endo conformation. The structures with 6-chloroguanosine and 8-bromoguanosine pointed out that the Cl-6 and Br-8 substrate modifications seem to be detrimental for catalysis and can be explored in the design of inhibitors for hexameric PNPs from pathogens. Our data also corroborated the competitive inhibition mechanism of hexameric PNPs by tubercidin and suggested that the acyclic nucleoside ganciclovir is a better inhibitor for hexameric PNPs than aciclovir. Furthermore, comparative structural analyses indicated that the replacement of Ser(90) by a threonine in the B. cereus hexameric adenosine phosphorylase (Thr(91)) is responsible for the lack of negative cooperativity of phosphate binding in this enzyme.

Actions of the Kunitz-type serine protease inhibitor Amblyomin-X on VEGF-A-induced angiogenesis

Amblyomin-X is a Kunitz-type serine protease inhibitor (Kunitz-type SPI) designed from the cDNA library of the Amblyomma cajennense tick, which displays in vivo anti-tumor activities. Here, the mechanisms of actions of Amblyomin-X in vascular endothelial growth factor A (VEGF-A)-induced angiogenesis were characterized. Topical application of Amblyomin-X (10 or 100 ng/10 mu l; each 48 h) inhibited VEGF-A-induced (10 ng/10 mu l; each 48 h) angiogenesis in the dorsal subcutaneous tissue in male Swiss mice. Moreover, similar effect was observed in the VEGF-A-induced angiogenesis in the chicken chorioallantoic membrane (CAM). Additional in vitro assays in t-End cells showed that Amblyomin-X treatment delayed the cell cycle, by maintaining them in G0/G1 phase, and inhibited cell proliferation and adhesion, tube formation and membrane expression of the adhesion molecule platelet-endothelial cell adhesion molecule-1 (PECAM-I), regardless of mRNA synthesis. Together, results herein reveal the role of Kunitz-type SPI on in vivo VEGF-A-induced angiogenesis, by exerting modulatory actions on endothelial cell proliferation and adhesion, especially on membrane expression of PECAM-1. These data provide further mechanisms of actions of Kunitz-type SPI, corroborating their relevance as scientific tools in the design of therapeutic molecules. (C) 2012 Elsevier Ltd. All rights reserved.

Comparison of the Clinical Expression of Patients with Ankylosing Spondylitis from Europe and Latin America

Objective. To compare the clinical, demographic, and serologic characteristics and the treatment of patients diagnosed with ankylosing spondylitis (AS) from Europe (EU) and Latin America (LA). Methods. We included 3439 patients from national registries: the Spanish Registry of Spondyloarthritis (REGISPONSER), the Belgian registry (ASPECT), and the Latin American Registry of Spondyloarthropathies (RESPONDIA). We selected patients with diagnosis of AS who met the modified New York classification criteria. Demographic, clinical, disease activity, functional, and metrological measurement data were recorded. Current treatment was recorded. The population was classified into 2 groups: patients with disease duration < 10 years and those with disease duration >= 10 years. A descriptive and comparative analysis of variables of both groups was carried out. Results. There were 2356 patients in EU group and 1083 in LA group. Prevalence of HLA-B27 was 71% in LA group and 83% in EU group (p < 0.001). We found a greater frequency of peripheral arthritis and enthesitis (p < 0.001) in the LA population; prevalence of arthritis was 57% in LA and 42% in EU, and for enthesitis, 54% and 38%. Except for treatment with anti-tumor necrosis factor (anti-TNF), the use of nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, and disease-modifying antirheumatic drugs (DMARD), and the association of anti-TNF and methotrexate use showed a significant difference (p < 0.001) in the 2 populations. Conclusion. The principal differences in the clinical manifestations of patients with AS from EU and LA were the greater frequency of peripheral arthritis and enthesitis in LA group, the higher percentage of HLA-B27 in EU group, and the form of treatment, with a greater use of NSAID, steroids, and DMARD in the LA group. (First Release Nov 15 2012; J Rheumatol 2012;39:2315-20; doi:10.3899/jrheum.110687)

Ethnic Influence in Clinical and Functional Measures of Brazilian Patients with Spondyloarthritis

Objective. Spondyloarthritides (SpA) can present different disease spectra according to ethnic background. The Brazilian Registry of Spondyloarthritis (RBE) is a nationwide registry that comprises a large databank on clinical, functional, and treatment data on Brazilian patients with SpA. The aim of our study was to analyze the influence of ethnic background in SpA disease patterns in a large series of Brazilian patients. Methods. A common protocol of investigation was prospectively applied to 1318 SpA patients in 29 centers distributed through the main geographical regions in Brazil. The group comprised whites (65%), African Brazilians (31.3%), and people of mixed origins (3.7%). Clinical and demographic variables and various disease index scores were compiled. Ankylosing spondylitis (AS) was the most frequent disease in the group (65.1%); others were psoriatic arthritis (18.3%), undifferentiated SpA (6.8%), enteropathic arthritis (3.7%), and reactive arthritis (3.4%). Results. White patients were significantly associated with psoriasis (p = 0.002), positive HLA-B27 (p = 0.014), and use of corticosteroids (p < 0.0001). Hip involvement (p = 0.02), axial inflammatory pain (p = 0.04), and radiographic sacroiliitis (p = 0.025) were associated with African Brazilian descent. Sex distribution, family history, and presence of peripheral arthritis, uveitis, dactylitis, urethritis, and inflammatory bowel disease were similar in the 3 groups, as well as age at disease onset, time from first symptom until diagnosis, and use of anti-tumor necrosis factor-a agents (p > 0.05). Schober test and thoracic expansion were similar in the 3 groups, whereas African Brazilians had higher Maastricht Ankylasing Spondylitis Enthesitis Scores (p = 0.005) and decreased lateral lumbar flexion (p = 0.003), while whites had a higher occiput-to-wall distance (p = 0.02). African Brazilians reported a worse patient global assessment of disease (p = 0.011). Other index scores and prevalence of work incapacity were similar in the 3 groups, although African Brazilians had worse performance in the Ankylosing Spondylitis Quality of Life questionnaire (p < 0.001). Conclusion. Ethnic background is associated with distinct clinical aspects of SpA in Brazilian patients. African Brazilian patients with SpA have a poorer quality of life and report worse disease compared to whites, (First Release Nov 1 2011; J Rheumatol 2012;39:141-7; doi:10.3899/jrheum.110372)

Anti-inflammatory Effects of Aerobic Exercise in Mice Exposed to Air Pollution

VIEIRA, R. D. P., A. C. TOLEDO, L. B. SILVA, F. M. ALMEIDA, N. R. DAMACENO-RODRIGUES, E. G. CALDINI, A. B. G. SANTOS, D. H. RIVERO, D. C. HIZUME, F. D. T. Q. S. LOPES, C. R. OLIVO, H. C. CASTRO-FARIA-NETO, M. A. MARTINS, P. H. N. SALDIVA, and M. DOLHNIKOFF. Anti-inflammatory Effects of Aerobic Exercise in Mice Exposed to Air Pollution. Med. Sci. Sports Exerc., Vol. 44, No. 7, pp. 1227-1234, 2012. Purpose: Exposure to diesel exhaust particles (DEP) results in lung inflammation. Regular aerobic exercise improves the inflammatory status in different pulmonary diseases. However, the effects of long-term aerobic exercise on the pulmonary response to DEP have not been investigated. The present study evaluated the effect of aerobic conditioning on the pulmonary inflammatory and oxidative responses of mice exposed to DEP. Methods: BALB/c mice were subjected to aerobic exercise five times per week for 5 wk, concomitantly with exposure to DEP (3 mg.mL (1); 10 mu L per mouse). The levels of exhaled nitric oxide, reactive oxygen species, cellularity, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were analyzed in bronchoalveolar lavage fluid, and the density of neutrophils and the volume proportion of collagen fibers were measured in the lung parenchyma. The cellular density of leukocytes expressing IL-1 beta, keratinocyte chemoattractant (KC), and TNF-alpha in lung parenchyma was evaluated with immunohistochemistry. The levels of IL-1 beta, KC, and TNF-alpha were also evaluated in the serum. Results: Aerobic exercise inhibited the DEP-induced increase in the levels of reactive oxygen species (P < 0.05); exhaled nitric oxide (P < 0.01); total (P < 0.01) and differential cells (P < 0.01); IL-6 and TNF-alpha levels in bronchoalveolar lavage fluid (P < 0.05); the level of neutrophils (P < 0.001); collagen density in the lung parenchyma (P < 0.05); the levels of IL-6, KC, and TNF-alpha in plasma (P < 0.05); and the expression of IL-1 beta, KC, and TNF-alpha by leukocytes in the lung parenchyma (P < 0.01). Conclusions: We conclude that long-term aerobic exercise presents protective effects in a mouse model of DEP-induced lung inflammation. Our results indicate a need for human studies that evaluate the pulmonary responses to aerobic exercise chronically performed in polluted areas.

Encefalite anti-receptor N-metil-D-aspartato na infância

OBJETIVO: Discutir o diagnóstico diferencial das encefalites além daquelas de etiologia infecciosa, e alertar os pediatras para a possibilidade do diagnóstico de encefalite anti-receptor N-metil-D-aspartato (rNMDA) na população pediátrica, destacando suas principais características clínicas. DESCRIÇÃO: Três pacientes apresentaram-se com uma síndrome neuropsiquiátrica inicial seguida de encefalopatia e transtornos de movimento. As características neuropsiquiátricas iniciais se desenvolveram ao longo de dias ou semanas, com mudanças comportamentais, ansiedade, confusão mental e regressão da fala. Em seguida, os pacientes evoluíram com distúrbios de movimento, caracterizados por coreoatetose ou distonia, acometendo a região orofacial e os membros. Após a exclusão das principais causas de encefalite, foram identificados anticorpos anti-rNMDA no soro e no líquido cefalorraquidiano. Não foram detectadas neoplasias durante a investigação etiológica. Os pacientes foram submetidos a imunossupressão, e dois deles tiveram uma recuperação neurológica completa. Um deles ainda apresenta uma postura distônica leve em um dos membros. COMENTÁRIOS: Os sinais clínicos de encefalite anti-rNMDA em crianças são semelhantes aos anteriormente descritos em adultos. Tumores geralmente não são detectados nessa idade. O diagnóstico de encefalite anti-rNMDA deve ser abordado após a exclusão de outras causas de encefalite na infância, como as de origem infecciosa. Pediatras devem estar atentos a essa condição autoimune passível de tratamento.

Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion

Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 mu mol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group. LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.

Infliximab partially impairs the anti-Mycobacterium tuberculosis immune responses of severe psoriasis patients with positive tuberculin skin-test

Background Infliximab and etarnecept are now widely used for treating severe psoriasis. However, these drugs, especially infliximab, increased the risk of tuberculosis reactivation. Surprisingly, epidemiological data suggest that the tuberculosis rate in patients taking infliximab in Sao Paulo State, Brazil, is similar to that of some developed, non-endemic countries. Objective The aim of this study was to better understand the effect of infliximab on Mycobacterium tuberculosis (Mtb) immune responses of psoriasis patients in an endemic setting (Brazil). Methods We evaluated the tuberculosis-specific immune responses of severe psoriasis patients and healthy individuals, both tuberculin skin test (TST) positive, in the presence/absence of infliximab. Patients had untreated severe psoriasis, no co-morbidities affecting the immune responses and a TST >10 mm. Healthy TST+ (>10 mm) individuals were evaluated in parallel. PBMC cultures from both groups were stimulated with different Mycobacterium tuberculosis (Mtb) antigens (ESAT-6, 85B and Mtb lysate) and phytohemagglutinin, with or without infliximab (5 mu g/mL). Parameters evaluated were TNF-alpha, IFN-gamma and IL-10 secretion by ELISA, overnight IFN-gamma ELISpot and lymphocyte proliferative response (LPR). Results Infliximab almost abolished TNF-alpha detection in PBMC supernatants of both groups. It also significantly reduced the LPR to phytohemagglutinin and the Mtb antigens as well as the IFN-gamma levels secreted into day 5 supernatants in both groups. There was no concomitant exaggerated IL-10 secretion that could account for the decreases in these responses. ELISpot showed that, contrasting with the central-memory responses above, infliximab did not affect effector-memory INF-gamma-releasing T-cell numbers. Conclusions Infliximab affected some, but not all aspects of the in vitro antituberculosis immune responses tested. The preserved effector-memory responses, putatively related to exposure to environmental mycobacteria, may help to explain the lower than expected susceptibility to tuberculosis reactivation in our setting. Received: 29 December 2010; Accepted: 9 March 2011

Curcumin requires tumor necrosis Factor α signaling to alleviate cognitive impairment elicited by Lipopolysaccharide

A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampusdependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl- D –aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.