A terapia endodôntica visa o selamento biológico do complexo sistema apical, contribuindo para isso, as substâncias usadas no tratamento e a resposta imune do paciente. A LILT tem mostrado atividade antiinflamatória, favorecendo o processo reparacional. Sendo assim, este trabalho objetivou analisar o efeito da LILT na atividade secretória de macrófagos, previamente ativados por IFN-? e LPS de E.coli, e estimulados por substâncias liberadas de três tipos de cimentos endodônticos, um a base de óxido de zinco e eugenol, outro a base de hidróxido de cálcio e um terceiro resinoso. A citotoxicidade dessas substâncias foi avaliada usando a técnica de análise do MTT. Macrófagos ativados foram estimulados por essas substâncias ou não (controle) e então, irradiados ou não (controle) e a secreção de proteínas próinflamatórias (interleucina-1 b, fator de necrose tumoral-a e metaloproteinase da matriz-1) foram analisadas pelo teste ELISA. As irradiações foram realizadas com um laser GaAlAs (780 nm, 70 mW, ponta da fibra de 4 mm2, 1.67 seg, 3 J/cm2). Foram usadas duas aplicações de irradiação com intervalo de 6 h. Os dados obtidos foram tratados por Análise de Variância, quando de distribuição normal, ou teste de Friedman, quando de distribuição não normal, com nível de significância de 5 % (p = 0,05). A viabilidade dos controles e células tratados pelos cimentos endodônticos foi similar. Produção de IL-1 b e TNF-a foram observadas. Houve alta produção de MMP-1. Entretanto, sem diferenças estatísticas entre os grupos experimentais. Os grupos irradiados apresentaram resultados similares aos não irradiados. Substâncias liberadas pelos cimentos endodônticos testados não se mostraram citotóxicas nas condições deste experimento. Essas substâncias, bem como a LILT, no parâmetro utilizado, não causam alteração na atividade de secreção de MMP-1, IL-1 b e TNF-a por macrófagos ativados. / The endodontic therapy seeks the dental root canal biological sealing, depending on substances used in this process and patient’s defense immune factors. LILT has shown an anti-inflammatory activity, improving the periapical repair process. This in vitro study aimed to analyze the effect of LILT at the secretory activity of macrophages previously activated by interferon-gamma and lypopolisaccharide from E.coli, and stimulated by substances leached from three endodontic sealers (zinc oxide-eugenol based, resinous and calcium hydroxide-based). Cytotoxicity of these substances was assessed by the MTT test. Activated macrophages were stimulated by the substances or not (control) and then, irradiated or not (control) and the secretion of pro-inflammatory proteins (interleukin-1 b, tumor necrosis factor-a and matrix metalloproteinase-1) was analyzed by ELISA test. The LILT was performed using a GaAlAs laser (780 nm, 70 mW, focal spot of 4.0 mm2, 1.67 sec, 3 J/cm2). Two irradiations with 6 h-intervals were done. The data was compared by either ANOVA test or Friedman’s test. The cell viabilities of controls and cells treated by the sealers were similar. Production of IL -1 b and TNF-a were observed. There was a high production of MMP-1. However, statistical differences were not observed amongst the groups. The irradiated groups presented results similar to those of non irradiated groups. Substances leached from the endodontic sealers are non cytotoxic at these experiments conditions . These substances, as well as the LILT, at the parameter used, were not able to change the secretion of MMP-1, IL-1 b e TNF-a by activated macrophages.

A terapia endodôntica visa o selamento biológico do complexo sistema apical, contribuindo para isso, as substâncias usadas no tratamento e a resposta imune do paciente. A LILT tem mostrado atividade antiinflamatória, favorecendo o processo reparacional. Sendo assim, este trabalho objetivou analisar o efeito da LILT na atividade secretória de macrófagos, previamente ativados por IFN-? e LPS de E.coli, e estimulados por substâncias liberadas de três tipos de cimentos endodônticos, um a base de óxido de zinco e eugenol, outro a base de hidróxido de cálcio e um terceiro resinoso. A citotoxicidade dessas substâncias foi avaliada usando a técnica de análise do MTT. Macrófagos ativados foram estimulados por essas substâncias ou não (controle) e então, irradiados ou não (controle) e a secreção de proteínas próinflamatórias (interleucina-1 b, fator de necrose tumoral-a e metaloproteinase da matriz-1) foram analisadas pelo teste ELISA. As irradiações foram realizadas com um laser GaAlAs (780 nm, 70 mW, ponta da fibra de 4 mm2, 1.67 seg, 3 J/cm2). Foram usadas duas aplicações de irradiação com intervalo de 6 h. Os dados obtidos foram tratados por Análise de Variância, quando de distribuição normal, ou teste de Friedman, quando de distribuição não normal, com nível de significância de 5 % (p = 0,05). A viabilidade dos controles e células tratados pelos cimentos endodônticos foi similar. Produção de IL-1 b e TNF-a foram observadas. Houve alta produção de MMP-1. Entretanto, sem diferenças estatísticas entre os grupos experimentais. Os grupos irradiados apresentaram resultados similares aos não irradiados. Substâncias liberadas pelos cimentos endodônticos testados não se mostraram citotóxicas nas condições deste experimento. Essas substâncias, bem como a LILT, no parâmetro utilizado, não causam alteração na atividade de secreção de MMP-1, IL-1 b e TNF-a por macrófagos ativados. / The endodontic therapy seeks the dental root canal biological sealing, depending on substances used in this process and patient’s defense immune factors. LILT has shown an anti-inflammatory activity, improving the periapical repair process. This in vitro study aimed to analyze the effect of LILT at the secretory activity of macrophages previously activated by interferon-gamma and lypopolisaccharide from E.coli, and stimulated by substances leached from three endodontic sealers (zinc oxide-eugenol based, resinous and calcium hydroxide-based). Cytotoxicity of these substances was assessed by the MTT test. Activated macrophages were stimulated by the substances or not (control) and then, irradiated or not (control) and the secretion of pro-inflammatory proteins (interleukin-1 b, tumor necrosis factor-a and matrix metalloproteinase-1) was analyzed by ELISA test. The LILT was performed using a GaAlAs laser (780 nm, 70 mW, focal spot of 4.0 mm2, 1.67 sec, 3 J/cm2). Two irradiations with 6 h-intervals were done. The data was compared by either ANOVA test or Friedman’s test. The cell viabilities of controls and cells treated by the sealers were similar. Production of IL -1 b and TNF-a were observed. There was a high production of MMP-1. However, statistical differences were not observed amongst the groups. The irradiated groups presented results similar to those of non irradiated groups. Substances leached from the endodontic sealers are non cytotoxic at these experiments conditions . These substances, as well as the LILT, at the parameter used, were not able to change the secretion of MMP-1, IL-1 b e TNF-a by activated macrophages.

A lesão granulomatosa é caracterizada como um agregado compacto de fagócitos maduros formado em resposta à um estímulo persistente. Os mediadores pró-inflamatórios da família da IL-1, ao promoverem a ativação da imunidade inata e o remodelamento tecidual descontrolados, geram a fisiopatologia da paracoccidioidomicose, doença pulmonar granulomatosa causada pelo fungo P. brasiliensis. A principal via inflamatória envolvida na secreção de IL-1?, IL-18 e IL-1? é a ativação dos inflammasomas, complexos protéicos conhecidos pela sua capacidade de ativar proteoliticamente a enzima caspase-1. Neste estudo abordamos os mecanismos subjacentes às vias canônica e não canônica do inflamassoma, avaliando a importância funcional das caspases 1, 11 e 8 na resistência do hospedeiro durante a infecção por P. brasiliensis. Demonstramos que a resposta imunológica protetora mediada pelo IFN-?, após a liberação de IL-18 pela via da caspase-1, é o principal mecanismo responsável pelo controle fúngico quando o dano celular desencadeado pelo fungo é reconhecido pelo inflamassoma de NLRP3. No entanto, apesar do papel importante da caspase-1 na maturação da IL-1?, a falta de caspase-1 apenas reduz parcialmente os níveis de IL-1? durante a infecção por P. brasiliensis. Ao contrário do esperado, a deficiência de caspase-11 não prejudicou a produção de IL-1?, mas em vez disso, preveniu, na célula, a morte por piroptose e a secreção IL-1?, citocina importante para restringir o crescimento fúngico através da síntese de IL-17. Por fim, observamos que a ativação de caspase-8 pela sinalização de dectina-1 / Syk, além de mediar a maturação da IL-1?, que acontece de maneira independente de caspase-1 e 11, é necessária também para o funcionamento eficiente da via canônica de caspase-1, demonstrando uma rede interligada entre as vias canônica de caspse-1 e não canônica de caspase-8 para coordenar o processamento da IL-1?. Em conjunto, nossos resultados mostram contribuições distintas das vias canônica e não canônica do inflamassoma na produção de citocinas da família da IL-1, enfatizam a versatilidade desta plataforma em recrutar várias proteínas efetoras para adequar a resposta imunológica antifúngica e evidenciam a complexidade envolvida nas interações patógeno-hospedeiro. / Granuloma is a lesion characterized by a compact aggregate of mature phagocytes arising in response to a persistent stimulus. By driving uncontrolled innate immunity and tissue remodelling, IL-1 family pro-inflammatory mediators govern the pathophysiology of paracoccidioidomycosis, a granulomatous lung disorders caused by Paracocccidioides brasiliensis. A major inflammatory pathway involved in IL-1?, IL-18 e IL-1? secretion is the activation of inflammasomes, large multimolecular complexes best known for their ability to control activation of the proteolytic enzyme caspase-1. In this study we addressed the mechanisms that underlie canonical and non-canonical inflammasome pathways, assessing the functional importance of caspase-1, caspase-11 and caspase-8 in the regulation of inflammasome-mediated host resistance during P. brasiliensis infection. We found that IFN-?-mediated protective immune response following by caspase-1- dependent IL-18 release after is the key mechanism responsible for the fungal control after P. brasiliensis-induced cell damage recognition by NLRP3 canonical inflammasome pathway. Nonetheless, despite the important role of caspase-1 in the IL-1? maturation, the lack of caspase-1 only partially reduced IL-1? levels during P. brasiliensis infection. Unlike caspase-1, caspase-11 deficiency did not impair IL-1? production, cytokine strictly secreted by canonical caspase-1 inflammasome pathway. Instead, P. brasiliensis-triggered caspase-11 activation in an ill-defined manner leads to a rapid pore-mediated cell lysis and is required for IL-1? production during P. brasiliensis infection. IL-1?, in turn, is important for promoting the restriction of fungal growth trough IL-17-based inflammation. Finally, the caspase-8 induction by dectin-1/Syk signaling besides playing a role in mediating the caspase-1/11-independent IL-1? maturation is also required to efficient canonical caspase-1 inflammasome pathway, demonstrating a connected network between non-canonical caspase-8 and canonical caspase-1 inflammasome pathways to coordinate IL-1?. Taken together, our results revealed distincts contributions of both canonical and non-canonical inflammasome pathways in IL-1 family cytokine production and emphasizes the versatility of this platform to recruit several effector proteins to tailor the antifungal immune response, sheding new light on the complexity of this hostpathogen interaction.

Opioids are powerful analgesics. Despite their high efficacy for the management of moderate to severe pain, their clinical utility is limited due to the occurrence of adverse effects. The main problem associated with opioid use is the differential rate of tolerance development to the various pharmacological effects of opioids, with tolerance to respiratory depression occurring at a slower rate than analgesic and euphoric effects. The development of analgesic tolerance, where the efficacy of the drug progressively diminishes with repeated administration, requires higher doses of the drug to achieve a maximum effect. Reports have implicated inflammation as a major driver of analgesic tolerance development. With surmounting evidence that the prototypical opioid, morphine induces pro-inflammatory cytokine release in the brain, spinal cord, and gastrointestinal tract, a question arises of whether pro-inflammatory cytokine release in the gut as a result of chronic morphine treatment is paralleled with the development of morphine antinociceptive tolerance. This dissertation investigated the rate at which antinociceptive tolerance to various doses of morphine developed to a different degree in the presence of colonic inflammation. Using a mouse model, colonic inflammation was induced with 2,4,6-Trinitrobenzenesulfonic acid (TNBS) and then the mice were pelleted with 25 mg, 50 mg (2x25), or 75 mg morphine pellet. Antinociceptive tolerance to morphine was determined in a warm-water tail-immersion assay upon an administration of a morphine challenge dose (10 mg/kg). Inflammatory cytokine expressions and protein levels were measured from whole colon using qPCR and ELISA, respectively. Morphine antinociceptive tolerance was significantly enhanced in the presence of colonic inflammation in a dose and time dependent manner. With a daily injection of 0.5 mg/kg peripheral opioid receptor antagonist 6β-N-heterocyclic substituted naltrexamine derivative (NAP), mice pelleted with 25 mg, 50 mg (2x25), or 75 mg morphine pellets were tested on day 5, 4, or 3, respectively. Tolerance to morphine as well as the enhanced tolerance observed in the presence of colonic inflammation was prevented with daily NAP treatment. However, NAP did not block morphine-induced or TNBS-induced inflammation. Collectively, our findings indicate that inflammation is a major modulator of morphine antinociceptive tolerance and peripheral opioid receptors may be responsible for mediating antinociceptive tolerance.

Pseudomonas aeruginosa-induced pneumonia is serious problem that results in severe inflammation response and high mortality in the host. Interleukin-1£] (IL-1£]) is one of the major extracellular proinflammatory cytokines thought to be involved in many acute and chronic lung diseases. To investigate the role of caspase-1, IL-1£] and macrophage inflammatory protein-2 (MIP-2) in P. aeruginosa pneumonia induced lung damage, C57BL/6 (WT) and CASP-1-/- mice were subjected to pneumonia induced by intratracheal injection of P. aeruginosa. The lung permeability, bacterial content in blood and lung, lung myeloperoxidase (MPO) activity, total cell counts and protein in bronchoalveolar lavage fluid (BALF), NF-£eB activation as well as expression of IL-1£] and MIP-2 were assayed at 8 hr after P. aeruginosa injection. The IL-1£] inhibitor, anakinra, was also used to evaluate the role of IL-1£]. P. aeruginosa injection increased the lung permeability, lung MPO activity, bacterial counts in blood, total cell counts and protein in BALF, NF-£eB activation and expression of IL-1£] and MIP-2 in WT mice; and these increases were all decreased by administration of anakinra in WT mice or in CASP-1-/- mice. Furthermore, the lung MPO activity, total protein in BALF and expression of IL-1£] and MIP-2 were decreased in CASP-1-/- ¡÷ WT but not in WT ¡÷ CASP-1-/- chimeric mice, suggesting that pneumonia induced lung damage and IL-1£] and MIP-2 expressions depend on caspase-1 signaling of the resident cells.

Grouper (Epinephelus coioides) is one of the important farmed fish in the southern Taiwan. However, grouper aquaculture in Taiwan has a serious problem of infection, especially in grouper larvae breeding stage. The infection resulted in very high mortality, which causes massive economic loss. Therefore, early detecting the presence of pathogen is critical for preventing epidemic outbreak. Interleukin-1 (IL-1) is one of proinflammatory cytokines that form a feedback control loop with anti-inflammatory cytokines to maintain the homeostasis of host immune response. The increase of IL-1 expression could be an indicator of pathogenic insult. In this study, total RNA of Epinephelus coioides fertilized egg was extracted for reverse transcription-polymerase chain reaction (RT-PCR) to amplify cDNA of IL -1£]. The cDNA amplified was then cloned into pGEX4T-3 for the expression and purification of GST-IL-1£] fusion protein. GST-IL-1£] fusion protein purified was then used to immunize New Zealand white rabbit for generation of antiserum against IL-1£]. Western blot result confirmed the specificity of antiserum as the immune serum, but not the preimmune serum, detected the immunogen GST-IL-1s. Further experiments using live Epinephelus coioides injected with or without lipopolysarcharides (LPS) further confirmed that this antiserum could detect a massive increase of IL-1£] protein after the injection of LPS in either protein lysate by western blotting or in frozen tissue section of head kidney by immunohistochemistry. In summary, we successfully generated a rabbit specific antiserum against IL-1£] of Epinephelus coioides , which could be a useful reagent for future analysis of fish immune response upon pathogen infection.

ABSTRACT Background: Palindromic rheumatism (PR) is the rare disease that generally occurs with multiple recurring attacks of painful inflammation affecting joints and adjacent tissues. The thesis attempts to characterize the association in 10 instances of the single nucleotide polymorphisms (SNPs) of tumor necrosis factor genes (TNF-£\, TNFRSF1A and TNFRSF1B), Interleukin-1£] genes and Palindromic rheumatism (PR). Methods: The genetic polymorphisms of TNF-£\, TNFR£L, TNFR£S and IL-1£] genes cluster were investigated among 56 PR patients identified from the Kaohsiung Veterans General Hospital (VGHKS, Kaohsiung, Taiwan) and compared with one hundred healthy subjects. The genotypes for ten SNPs in the TNF-£\, TNFRSF1A, TNFRSF1B and IL-1£] genes among these 156 individuals were examined. Results: Experiments indicate significant count of the TNFRSF1A+36 AG genotype in PR patients (OR=4.8, 95%CI=1.8-13.0, p=0.002) and TNFRSF1A+36G allele (OR=3.94, 95%CI=1.59-9.79, p=0.003).The results also have remarkable correlation with TNFRSF1B haplotype +676/+1663 T/A (OR=2.12, CI=1.2-3.8, p=0.010). However, on significant differences were found for all the TNF-£\and IL-1£]polymorphisms. Conclusions: Genetic polymorphisms in TNF-£\ receptors are associated with susceptibility and severity of the inflammatory response in the PR patients.

Previous studies show that coronary artery disease (CAD) is a multi-factors and chronic inflammatory disease, and is associated with lipid metabolism. IL-1ra is a naturally occurring anti-inflammatory molecules that block the action of IL-1. However, little is known about the imbalance between IL-1ra and inflammatory mediators in CAD. We attempted to investigate the relationships between inflammatory mediators and serum IL-1ra levels in patients with CAD. In 95 patients with angiographically defined CAD, and 70 healthy controls were studied in a case-control manner. Serum levels of cytokines and the risk factor of CAD were examined. Polymorphisms for IL-1ra gene were detected by PCR, and genotypes and allelic frequencies in both groups were compared. Our major finding include: (1) The risk factors such as elevated BMI, systolic BP, smoking, hypertension, blood glucose, and TG was more frequently found in the CAD group than the control group ( p < 0.001). However, the HDL-C and bilirubin were significantly higher in control group than the CAD group. (2) The relative risk of those in the highest quartile of ratio of LDL-C to HDL-C, TC to HDL-C, and TG to HDL-C were significantly elevated. ( OR = 2.98, p < 0.01; OR = 5.31, p <0.001; OR = 8.43, p < 0.001 respectively) (3) Five different inflammatory markers were significantly elevated including IL-1ra, hs-CRP, IL-6, leukocyte count, and neutrophil percentage between healthy controls and CAD patients. ( p < 0.01) (4) Levels of IL-1ra and other variables such as blood glucose, BMI, TG, IL-6, hs-CRP, and leukocyte count has significantly correlated, and were inversed correlation in bilirubin, and HDL-C in all study subjects. ( p < 0.01) (5) In the multiple logistic regression analysis, adjustment was made for variables. The relative risk of CAD for the highest quartile of IL-1ra, as compared with the lowest quartile, had an Odds ratio 2.57 ( 95% confidence intervals, 1.12 - 5.91, p = 0.026 ) increase in risk for CAD. (6) Similar results were obtained hs-CRP, IL-6 in the highest quartile were increase risk for future CAD. ( OR = 5.86 and 5.79 respectively; p < 0.001) (7) The join effect cytokines of hs-CRP, IL-6, IL-1ra concentrations may play important role in CAD risk. ( OR = 10.19, p < 0.001 ) (8) In addition, IL-1ra allele 2 genotype and allelic frequencies were no significant association with increase in IL-1ra with CAD. In conclusion, we find a significant association of elevated IL-1ra levels in the patients with CAD. Thus, these results support the hypothesis that inflammation, anti-inflammation cytokines and lipoprotein metabolism provide a useful marker for predicting the development of CAD events.

A lesão granulomatosa é caracterizada como um agregado compacto de fagócitos maduros formado em resposta à um estímulo persistente. Os mediadores pró-inflamatórios da família da IL-1, ao promoverem a ativação da imunidade inata e o remodelamento tecidual descontrolados, geram a fisiopatologia da paracoccidioidomicose, doença pulmonar granulomatosa causada pelo fungo P. brasiliensis. A principal via inflamatória envolvida na secreção de IL-1?, IL-18 e IL-1? é a ativação dos inflammasomas, complexos protéicos conhecidos pela sua capacidade de ativar proteoliticamente a enzima caspase-1. Neste estudo abordamos os mecanismos subjacentes às vias canônica e não canônica do inflamassoma, avaliando a importância funcional das caspases 1, 11 e 8 na resistência do hospedeiro durante a infecção por P. brasiliensis. Demonstramos que a resposta imunológica protetora mediada pelo IFN-?, após a liberação de IL-18 pela via da caspase-1, é o principal mecanismo responsável pelo controle fúngico quando o dano celular desencadeado pelo fungo é reconhecido pelo inflamassoma de NLRP3. No entanto, apesar do papel importante da caspase-1 na maturação da IL-1?, a falta de caspase-1 apenas reduz parcialmente os níveis de IL-1? durante a infecção por P. brasiliensis. Ao contrário do esperado, a deficiência de caspase-11 não prejudicou a produção de IL-1?, mas em vez disso, preveniu, na célula, a morte por piroptose e a secreção IL-1?, citocina importante para restringir o crescimento fúngico através da síntese de IL-17. Por fim, observamos que a ativação de caspase-8 pela sinalização de dectina-1 / Syk, além de mediar a maturação da IL-1?, que acontece de maneira independente de caspase-1 e 11, é necessária também para o funcionamento eficiente da via canônica de caspase-1, demonstrando uma rede interligada entre as vias canônica de caspse-1 e não canônica de caspase-8 para coordenar o processamento da IL-1?. Em conjunto, nossos resultados mostram contribuições distintas das vias canônica e não canônica do inflamassoma na produção de citocinas da família da IL-1, enfatizam a versatilidade desta plataforma em recrutar várias proteínas efetoras para adequar a resposta imunológica antifúngica e evidenciam a complexidade envolvida nas interações patógeno-hospedeiro. / Granuloma is a lesion characterized by a compact aggregate of mature phagocytes arising in response to a persistent stimulus. By driving uncontrolled innate immunity and tissue remodelling, IL-1 family pro-inflammatory mediators govern the pathophysiology of paracoccidioidomycosis, a granulomatous lung disorders caused by Paracocccidioides brasiliensis. A major inflammatory pathway involved in IL-1?, IL-18 e IL-1? secretion is the activation of inflammasomes, large multimolecular complexes best known for their ability to control activation of the proteolytic enzyme caspase-1. In this study we addressed the mechanisms that underlie canonical and non-canonical inflammasome pathways, assessing the functional importance of caspase-1, caspase-11 and caspase-8 in the regulation of inflammasome-mediated host resistance during P. brasiliensis infection. We found that IFN-?-mediated protective immune response following by caspase-1- dependent IL-18 release after is the key mechanism responsible for the fungal control after P. brasiliensis-induced cell damage recognition by NLRP3 canonical inflammasome pathway. Nonetheless, despite the important role of caspase-1 in the IL-1? maturation, the lack of caspase-1 only partially reduced IL-1? levels during P. brasiliensis infection. Unlike caspase-1, caspase-11 deficiency did not impair IL-1? production, cytokine strictly secreted by canonical caspase-1 inflammasome pathway. Instead, P. brasiliensis-triggered caspase-11 activation in an ill-defined manner leads to a rapid pore-mediated cell lysis and is required for IL-1? production during P. brasiliensis infection. IL-1?, in turn, is important for promoting the restriction of fungal growth trough IL-17-based inflammation. Finally, the caspase-8 induction by dectin-1/Syk signaling besides playing a role in mediating the caspase-1/11-independent IL-1? maturation is also required to efficient canonical caspase-1 inflammasome pathway, demonstrating a connected network between non-canonical caspase-8 and canonical caspase-1 inflammasome pathways to coordinate IL-1?. Taken together, our results revealed distincts contributions of both canonical and non-canonical inflammasome pathways in IL-1 family cytokine production and emphasizes the versatility of this platform to recruit several effector proteins to tailor the antifungal immune response, sheding new light on the complexity of this hostpathogen interaction.

Inflammation is a homeostatic response to tissue injury or infection, which is normally short- lived and quickly resolves to limit tissue damage. In contrast, chronic inflammation has been linked to a variety of human diseases, including cancers such as glioblastoma multiforme (GBM). GBMs are very aggressive tumors with very low patient survival rates, which have not improved in several decades. GBM tumors are characterized by necrosis and profound inflammation; with cytokines secreted by both GBM cells and the tumor microenvironment. The mechanisms by which chronic inflammation develops and persists in GBM regardless of multiple anti-inflammatory feedback loops remain elusive. This project identifies a molecular switch which promotes chronic inflammation in GBM, but not primary human astrocytes.