Tumor necrosis factor-alpha (TNF-α) regulates Toll-like receptor 2 (TLR2) expression in microglia

ABSTRACT The receptor activator of NF-κB ligand (RANKL) and the proinflammatory cytokines are believed to play important roles in osteoclastogenesis. We recently reported that the innate immune recognition receptor, Toll-like receptor 2 (TLR2), is crucial for inflammatory bone loss in response to infection by Porphyromonas gingivalis, the primary organism associated with chronic inflammatory periodontal disease. However, the contribution of macrophage-expressed TLRs to osteoclastogenesis has not been defined. In this study, we defined a requirement for TLR2 in tumor necrosis factor-alpha (TNF-α)-elicited osteoclastogenesis in response to exposure to P. gingivalis. Culture supernatant (CS) fluids from P. gingivalis-stimulated macrophages induced bone marrow macrophage-derived osteoclastogenesis. This activity was dependent on TNF-α and occurred independently of RANKL, interleukin-1β (IL-1β), and IL-6. CS fluids from P. gingivalis-stimulated TLR2−/− macrophages failed to express TNF-α, and these fluids induced significantly less osteoclast formation compared with that of the wild-type or the TLR4−/− macrophages. In addition, P. gingivalis exposure induced up-regulation of TLR2 expression on the cell surface of macrophages, which was demonstrated to functionally react to reexposure to P. gingivalis, as measured by a further increase in TNF-α production. These results demonstrate that macrophage-dependent TLR2 signaling is crucial for TNF-α-dependent/RANKL-independent osteoclastogenesis in response to P. gingivalis infection. Furthermore, the ability of P. gingivalis to induce the cell surface expression of TLR2 may contribute to the chronic inflammatory state induced by this pathogen.

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Lipoteichoic Acids from Lactobacillus Strains Elicit Strong Tumor Necrosis Factor Alpha-Inducing Activities in Macrophages through Toll-Like Receptor 2

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.2.259-266.2003 ◽

2003 ◽

Vol 10 (2) ◽

pp. 259-266 ◽

Cited By ~ 156

Author(s):

Tetsuya Matsuguchi ◽

Akimitsu Takagi ◽

Takeshi Matsuzaki ◽

Masato Nagaoka ◽

Kimika Ishikawa ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Toll Like Receptor 2 ◽

Factor Alpha ◽

Necrosis Factor ◽

Lipoteichoic Acids

ABSTRACT Lactobacilli are nonpathogenic gram-positive inhabitants of microflora. At least some Lactobacillus strains have been postulated to have health beneficial effects, such as the stimulation of the immune system. Here we examined the stimulatory effects of lactobacilli on mouse immune cells. All six heat-killed Lactobacillus strains examined induced the secretion of tumor necrosis factor alpha (TNF-α) from mouse splenic mononuclear cells, albeit to various degrees. When fractionated subcellular fractions of Lactobacillus casei were tested for NF-κB activation and TNF-α production in RAW264.7, a mouse macrophage cell line, the activity was found to be as follows: protoplast > cell wall ≫ polysaccharide-peptidoglycan complex. Both crude extracts and purified lipoteichoic acids (LTAs) from two Lactobacillus strains, L. casei and L. fermentum, significantly induced TNF-α secretion from RAW264.7 cells and splenocytes of C57BL/6, C3H/HeN, and C3H/HeJ mice but not from splenocytes of C57BL/6 TLR2 −/− mice. Lactobacillus LTA induced activation of c-Jun N-terminal kinase activation in RAW264.7 cells. Furthermore, in HEK293T cells transected with a combination of CD14 and Toll-like receptor 2 (TLR2), NF-κB was activated in response to Lactobacillus LTA. Taken together, these data suggest that LTAs from lactobacilli elicit proinflammatory activities through TLR2.

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Glucocorticoids and Tumor Necrosis Factor Alpha Cooperatively Regulate Toll-Like Receptor 2 Gene Expression

Molecular and Cellular Biology ◽

10.1128/mcb.24.11.4743-4756.2004 ◽

2004 ◽

Vol 24 (11) ◽

pp. 4743-4756 ◽

Cited By ~ 102

Author(s):

Marcela A. Hermoso ◽

Tetsuya Matsuguchi ◽

Kathleen Smoak ◽

John A. Cidlowski

Keyword(s):

Innate Immunity ◽

Transcription Factors ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Toll Like Receptor 2 ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) and glucocorticoids are widely recognized as mutually antagonistic regulators of adaptive immunity and inflammation. Surprisingly, we show here that they cooperatively regulate components of innate immunity. The Toll-like receptor 2 (TLR2) gene encodes a transmembrane receptor critical for triggering innate immunity. Although TLR2 mRNA and protein are induced by inflammatory molecules such as TNF-α, we show that TLR2 is also induced by the anti-inflammatory glucocorticoids in cells where they also regulate MKP-1 mRNA and protein levels. TNF-α and glucocorticoids cooperate to regulate the TLR2 promoter, through the involvement of a 3′ NF-κB site, a STAT-binding element, and a 3′ glucocorticoid response element (GRE). Molecular studies show that the IκBα superrepressor or a STAT dominant negative element prevented TNF-α and dexamethasone stimulation of TLR2 promoter. Similarly, an AF-1 deletion mutant of glucocorticoid receptor or ablation of a putative GRE notably reduced the cooperative regulation of TLR2. Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-α and dexamethasone. Together, these studies define novel signaling mechanism for these three transcription factors, with a profound impact on discrimination of innate and adaptive immune responses.

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Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses

Infection and Immunity ◽

10.1128/iai.71.8.4456-4462.2003 ◽

2003 ◽

Vol 71 (8) ◽

pp. 4456-4462 ◽

Cited By ~ 29

Author(s):

Ursula Deiters ◽

Marina Gumenscheimer ◽

Chris Galanos ◽

Peter F. Mühlradt

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Potential Candidate ◽

Toll Like Receptor ◽

Cross Tolerance ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Patients or experimental animals previously exposed to lipopolysaccharide (LPS) become tolerant to further LPS challenge. We investigated the potential of the macrophage-activating lipopeptide 2 (MALP-2) to induce in vivo cross tolerance to tumor necrosis factor alpha (TNF-α) and LPS. MALP-2-induced tolerance could be of practical interest, as MALP-2 proved much less pyrogenic in rabbits than LPS. Whereas LPS signals via Toll-like receptor 4 (TLR4), MALP-2 uses TLR2 and TLR6. LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2. No biologically active TNF-α could be detected in the serum of MALP-2-treated animals when challenged with LPS 24 or 72 h later, whereas suppression of LPS-dependent interleukin (IL)-6 lasted for only 24 h. Protection from lethal TNF-α shock was studied in galactosamine-treated mice. Dose dependently, MALP-2 prevented death from lethal TNF-α doses in TLR4−/− but not in TLR2−/− mice, with protection lasting from 5 to 24 h. To assay protection from LPS, mice were pretreated with MALP-2 doses of up to 10 μg. Five and 24 h later, the animals were simultaneously sensitized and challenged by intravenous coinjection of galactosamine and a lethal dose of 50 ng of LPS. There was only limited protection (four of seven mice survived) when mice were challenged 5 h after MALP-2 pretreatment, and no protection when mice were challenged at later times. The high effectiveness of MALP-2 in suppressing TNF-α, the known ways of biological inactivation, and low pyrogenicity make MALP-2 a potential candidate for clinical use.

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Toxoplasma gondii Inhibits Toll-Like Receptor 4 Ligand-Induced Mobilization of Intracellular Tumor Necrosis Factor Alpha to the Surface of Mouse Peritoneal Neutrophils

Infection and Immunity ◽

10.1128/iai.01573-05 ◽

2006 ◽

Vol 74 (7) ◽

pp. 4274-4281 ◽

Cited By ~ 12

Author(s):

Soumaya Bennouna ◽

Woraporn Sukhumavasi ◽

Eric Y. Denkers

Keyword(s):

Toxoplasma Gondii ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Toll Like Receptor ◽

Inhibitory Effects ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Neutrophils are well-known to rapidly respond to infection through chemotactic infiltration at sites of inflammation, followed by rapid release of microbicidal molecules, chemokines, and proinflammatory cytokines. For tumor necrosis factor alpha (TNF-α), we recently found that neutrophils contain intracellular pools of the cytokine and display the capacity to upregulate transcriptional activity of the gene during lipopolysaccharide (LPS) stimulation. We now show that triggering of mouse peritoneal neutrophils with Toll-like receptor 2 (TLR2), TLR4, and TLR9 ligands, but not ligands of TLR3, induces upregulation of surface membrane TNF-α. However, neutrophils infected with the protozoan Toxoplasma gondii displayed an inability to respond fully in terms of TLR ligand-induced increases in membrane TNF-α expression. Infected neutrophils failed to display decreased levels of intracellular TNF-α upon LPS exposure. In contrast to intermediate inhibitory effects in nontreated neutrophils, T. gondii induced a complete blockade in LPS-induced surface TNF-α expression in the presence of the protein synthesis inhibitor cycloheximide. Despite these inhibitory effects, the parasite did not affect LPS-induced upregulation of TNF-α gene transcription. Collectively, the results show that Toxoplasma prevents TLR ligand-triggered mobilization of TNF-α to the neutrophil surface, revealing a novel immunosuppressive activity of the parasite.

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Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy: a systematic review and updated meta-analysis.

Ophthalmic Research ◽

10.1159/000513586 ◽

2020 ◽

Author(s):

Wenna Gao ◽

Ruilin Zhu ◽

liu yang

Keyword(s):

Diabetic Retinopathy ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Meta Analysis ◽

Entire Group ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

Background: Mounting evidence has suggested tumor necrosis factor-alpha (TNF-α) can promote the development of diabetic retinopathy (DR), and TNF-α gene variants may influence DR risk. However, the results are quite different. Objectives: To comprehensively address this issue, we performed the meta-analysis to evaluate the association of TNF-α-308 G/A and -238 G/A polymorphism with DR. Method: Data were retrieved in a systematic manner and analyzed using STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Allelic and genotypic comparisons between cases and controls were evaluated. Results: For the TNF-α-308 G/A polymorphism, overall analysis suggested a marginal association with DR [the OR(95%CI) of (GA versus GG), (GA + AA) versus GG, and (A versus G) are 1.21(1.04, 1.41), 1.20(1.03, 1.39), and 1.14(1.01, 1.30), respectively]. And the subgroup analysis indicated an enhanced association among the European population. For the TNF-α-238 G/A polymorphism, there was mild correlation in the entire group [the OR(95%CI) of (GA versus GG) is 1.55(1.14,2.11) ], which was strengthened among the Asian population. Conclusion: The meta-analysis suggested that -308 A and -238 A allele in TNF-α gene potentially increased DR risk and showed a discrepancy in different ethnicities.

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Analysis of Subcellular RNA Fractions Revealed a Transcription-Independent Effect of Tumor Necrosis Factor Alpha on Splicing, Mediated by Spt5

Molecular and Cellular Biology ◽

10.1128/mcb.01117-15 ◽

2016 ◽

Vol 36 (9) ◽

pp. 1342-1353 ◽

Cited By ~ 10

Author(s):

Gil Diamant ◽

Tal Eisenbaum ◽

Dena Leshkowitz ◽

Rivka Dikstein

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Independent Effect ◽

Necrosis Factor Alpha ◽

Pol Ii ◽

Tnf Α ◽

Factor Alpha ◽

Induced Genes ◽

Necrosis Factor

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) modulates the expression of many genes, primarily through activation of NF-κB. Here, we examined the global effects of the elongation factor Spt5 on nascent and mature mRNAs of TNF-α-induced cells using chromatin and cytosolic subcellular fractions. We identified several classes of TNF-α-induced genes controlled at the level of transcription, splicing, and chromatin retention. Spt5 was found to facilitate splicing and chromatin release in genes displaying high induction rates. Further analysis revealed striking effects of TNF-α on the splicing of 25% of expressed genes; the vast majority were not transcriptionally induced. Splicing enhancement of noninduced genes by TNF-α was transient and independent of NF-κB. Investigating the underlying basis, we found that Spt5 is required for the splicing facilitation of the noninduced genes. In line with this, Spt5 interacts with Sm core protein splicing factors. Furthermore, following TNF-α treatment, levels of RNA polymerase II (Pol II) but not Spt5 are reduced from the splicing-induced genes, suggesting that these genes become enriched with a Pol II-Spt5 form. Our findings revealed the Pol II-Spt5 complex as a highly competent coordinator of cotranscriptional splicing.

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HSP70 Induction by ING Proteins Sensitizes Cells to Tumor Necrosis Factor Alpha Receptor-Mediated Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.01538-06 ◽

2006 ◽

Vol 26 (24) ◽

pp. 9244-9255 ◽

Cited By ~ 43

Author(s):

Xiaolan Feng ◽

Shirin Bonni ◽

Karl Riabowol

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Kinase Inhibitor ◽

Heat Shock Gene ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Primary Fibroblasts ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-α), and p33ING1b protein showed synergy with TNF-α in inducing apoptosis, which correlated with reduced NF-κB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-α-mediated apoptosis by binding I-κΒ kinase gamma and impairing NF-κB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-κB survival pathway important in hypoxia and angiogenesis.

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Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

Journal of Virology ◽

10.1128/jvi.00362-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7790-7798 ◽

Cited By ~ 26

Author(s):

Marlynne Q. Nicol ◽

Jean-Marie Mathys ◽

Albertina Pereira ◽

Kevin Ollington ◽

Michael H. Ieong ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Innate Immune ◽

Hiv Positive ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Immunodeficiency Virus ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

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Comparative Analysis of Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Activity in Serum and Lethality in Mice and Rabbits Pretreated with the Staphylococcal Superantigen Toxic Shock Syndrome Toxin 1

Infection and Immunity ◽

10.1128/iai.69.11.7169-7172.2001 ◽

2001 ◽

Vol 69 (11) ◽

pp. 7169-7172 ◽

Cited By ~ 37

Author(s):

Martin M. Dinges ◽

Patrick M. Schlievert

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Host Susceptibility ◽

Necrosis Factor Alpha ◽

Lethal Effects ◽

Tnf Α ◽

Factor Alpha ◽

Toxic Shock Syndrome Toxin ◽

Necrosis Factor

ABSTRACT Host susceptibility to lipopolysaccharide (LPS) is correlated with the levels of circulating tumor necrosis factor alpha (TNF-α) that develop in response to circulating LPS. Mice are resistant, relative to rabbits, to the lethal effects of LPS. This study indicates that mice and rabbits are equally sensitive to the lethal effects of circulating TNF-α but that mice are more resistant than rabbits to the induction of circulating TNF-α by LPS.

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