A fagocitose de células apoptóticas, também denominada eferocitose, é um processo dinâmico e de fundamental importância para homeostase dos tecidos após uma injúria. Estudos demonstraram previamente que a fagocitose de células apoptóticas promove a síntese de mediadores anti-inflamatórios como PGE2, TGF-? e IL-10, podendo resultar num microambiente supressor e aumento da susceptibilidade do hospedeiro contra agentes infecciosos. Entretanto, a fagocitose de células apoptóticas infectadas por células dendríticas promove a geração não apenas de citocinas anti-inflamatórias como TGF-?, mas também de IL-6 e IL-23, levando a um efeito imunoestimulador, a diferenciação de células Th17. A atuação da PGE2 na imunidade adaptativa vem sendo investigada quanto à diferenciação e ativação de linfócitos Th1, Treg e Th17. Nossos resultados demonstram que a fagocitose de células apoptóticas infectadas com E. coli promove a ativação e migração de células dendríticas, assim como a produção de citocinas pró- e anti-inflamatórias e altos níveis de PGE2. No entanto, diferente da hipótese inicial, a presença de altas concentrações de PGE2 inibe drasticamente a diferenciação de células Th17 no contexto de fagocitose de células apoptóticas infectadas com E. coli por células dendríticas, in vitro. O tratamento de linfócitos T CD4+naive com antagonistas e agonistas de EP2/EP4 demonstram que o efeito supressor de PGE2 é mediado primordialmente pelo receptor EP4. Por fim, nossos resultados in vivo comprovam os resultados obtidos in vitro, demonstrando o papel supressor de PGE2 na diferenciação de células Th17 no contexto de fagocitose de células apoptóticas infectadas em modelo de infecção pulmonar. / The phagocytosis of apoptotic cells, also called efferocytosis, is a dynamic process critical for tissue homeostasis after injury. We and other groups previously have shown that phagocytosis of apoptotic cells promotes the synthesis of anti-inflammatory mediators such as PGE2, TGF-? and IL-10, that may result in the suppression of host defense against microorganisms. However, an elegant study using infected apoptotic cells showed that phagocytosis of these cells promote not only the generation of anti-inflammatory cytokines such as TGF-? but also IL-6 and IL-23, resulting in an immunostimulatory effect, the differentiation of Th17 cells. The role of PGE2 in adaptive immunity has been investigated regarding differentiation and activation of Th1, Th17 and Treg. Our results demonstrate that engulfment of E.coli infected apoptotic cells promotes the activation and migration of dendritic cells as well as production of pro and anti-inflammatory cytokines together with high levels of PGE2. However, differing from our hypothesis, high levels of PGE2 inhibits drastically the differentiation of Th17 cells on the context of engulfment of E.coli infected apoptotic cells by dendritic cells in vitro. The treatment of T CD4+naive cells with antagonist or agonists of EP2/EP4 receptors demonstrates the suppressor effect is mainly mediated by EP4 receptor. Finally, the instillation of E.coli infected apoptotic cells in E.coli infected animals resulted on modest Th17 increase but treatment with cox inhibitor increased Th17 cell differentiation. Therefore, our in vivo results prove the in vitro results.

A fagocitose de células apoptóticas, também denominada eferocitose, é um processo dinâmico e de fundamental importância para homeostase dos tecidos após uma injúria. Estudos demonstraram previamente que a fagocitose de células apoptóticas promove a síntese de mediadores anti-inflamatórios como PGE2, TGF-? e IL-10, podendo resultar num microambiente supressor e aumento da susceptibilidade do hospedeiro contra agentes infecciosos. Entretanto, a fagocitose de células apoptóticas infectadas por células dendríticas promove a geração não apenas de citocinas anti-inflamatórias como TGF-?, mas também de IL-6 e IL-23, levando a um efeito imunoestimulador, a diferenciação de células Th17. A atuação da PGE2 na imunidade adaptativa vem sendo investigada quanto à diferenciação e ativação de linfócitos Th1, Treg e Th17. Nossos resultados demonstram que a fagocitose de células apoptóticas infectadas com E. coli promove a ativação e migração de células dendríticas, assim como a produção de citocinas pró- e anti-inflamatórias e altos níveis de PGE2. No entanto, diferente da hipótese inicial, a presença de altas concentrações de PGE2 inibe drasticamente a diferenciação de células Th17 no contexto de fagocitose de células apoptóticas infectadas com E. coli por células dendríticas, in vitro. O tratamento de linfócitos T CD4+naive com antagonistas e agonistas de EP2/EP4 demonstram que o efeito supressor de PGE2 é mediado primordialmente pelo receptor EP4. Por fim, nossos resultados in vivo comprovam os resultados obtidos in vitro, demonstrando o papel supressor de PGE2 na diferenciação de células Th17 no contexto de fagocitose de células apoptóticas infectadas em modelo de infecção pulmonar. / The phagocytosis of apoptotic cells, also called efferocytosis, is a dynamic process critical for tissue homeostasis after injury. We and other groups previously have shown that phagocytosis of apoptotic cells promotes the synthesis of anti-inflammatory mediators such as PGE2, TGF-? and IL-10, that may result in the suppression of host defense against microorganisms. However, an elegant study using infected apoptotic cells showed that phagocytosis of these cells promote not only the generation of anti-inflammatory cytokines such as TGF-? but also IL-6 and IL-23, resulting in an immunostimulatory effect, the differentiation of Th17 cells. The role of PGE2 in adaptive immunity has been investigated regarding differentiation and activation of Th1, Th17 and Treg. Our results demonstrate that engulfment of E.coli infected apoptotic cells promotes the activation and migration of dendritic cells as well as production of pro and anti-inflammatory cytokines together with high levels of PGE2. However, differing from our hypothesis, high levels of PGE2 inhibits drastically the differentiation of Th17 cells on the context of engulfment of E.coli infected apoptotic cells by dendritic cells in vitro. The treatment of T CD4+naive cells with antagonist or agonists of EP2/EP4 receptors demonstrates the suppressor effect is mainly mediated by EP4 receptor. Finally, the instillation of E.coli infected apoptotic cells in E.coli infected animals resulted on modest Th17 increase but treatment with cox inhibitor increased Th17 cell differentiation. Therefore, our in vivo results prove the in vitro results.

Macrophages are cells of the innate immune system that can be found in large quantities in cancer tumors and affect cancer progression by regulating growth and invasiveness of cancer cells. There are two main phenotypes of macrophages denoted M1 and M2. In this thesis, the M1 and M2 phenotype of human macrophages were characterized, and effects of the macrophages on the growth and invasiveness of colon and lung cancer cells were studied. Macrophages of the M1 phenotype, but not the M2 phenotype, inhibited growth of both colon and lung cancer cells, and the inhibition for some of the cancer cell lines was induced by cell cycle arrest in the G1/G0 and/or G2/M cell cycle phases. In the colon cancer cell line, the macrophage induced cell cycle arrest was found to attenuate the cytotoxic effect of the chemotherapeutic drug 5-FU. Macrophages were also shown to express high levels of proteases (matrix metalloproteinase-2 and 9) and high levels of proteins of the urokinase-type plasminogen activator (uPA) system, in comparison to the lung cancer cell lines studied. Expression of these has been found to predict poor outcome in lung cancer, and the results suggest macrophages to be important contributors of these in lung tumors. Furthermore, the M1 phenotype was found to express higher levels of the uPA receptor than the M2 phenotype. Prostaglandin E2 (PGE2) is a potent inflammatory molecule expressed by e.g. macrophages and monocytes, and inhibition of its expression has been shown to reduce the risk of colon cancer. Green tea and black tea was found to be potent inhibitors of PGE2 formation in human monocytes, and the inhibitory effects of green tea was likely due to its content of the polyphenol epigallocatechin gallate. Rooibos tea also inhibited PGE2 formation, but was less potent than green and black tea. The primary mechanism for the inhibition was via inhibition of expression of enzymes in the PGE2 formation pathway, and primarily microsomal prostaglandin synthase-1. / Macrophages are cells of the immune system often found in large numbers in cancer tumors. They affect multiple aspects of cancer progression, including growth and spread of cancer cells, and the efficacy of treatments. There are two major macrophage phenotypes denoted M1 and M2, that have mainly pro- and anti-inflammatory properties, respectively. In this thesis, M1 and M2 macrophages were characterized and effects of them on different aspects of cancer progression were studied using culture of colon, and lung cancer cells. The M1 phenotype inhibited proliferation of cancer cells from both colon and lung. The growth inhibition was for some cell lines accompanied by cell cycle arrest. The macrophage induced cell cycle arrest was found to protect colon cancer cells from the cytostatic drug 5-fluorouracil. Prostaglandin E2 (PGE2) contributes to colon cancer development and treatment of monocytes with tea extracts inhibited PGE2 formation via inhibition of expression of microsomal prostaglandin E synthase-1. Proteases can degrade the extracellular matrix of a tumor to facilitate cancer cell invasion and metastasis. The M1 and M2 phenotypes of macrophages expressed several protease activity related genes to a greater extent than lung cancer cells, and M1 more so than the M2 phenotype.

Univ., Diss., 2006--Frankfurt (Main) / Zsfassung in engl. und dt. Sprache

In dieser Studie wurde untersucht, ob die durch Ischämie (45min clamping) induzierte Herunterregulation der Sekretion organischer Anionen, wie postuliert, zu einer verminderten Ausscheidung von PGE2 führt und wie sich die Relation zu Inulin und PAH-Clearance verhält. Es wurde weiterhin untersucht, ob die Medikation mit Nebivolol (2,5mg, 5mg und 10 mg) oder Metoprolol Tartrat (47,5mg) einen positiven Effekt auf das renale Outcome, unter Berücksichtigung des Einflusses auf die PGE2- Ausscheidung, hat. PGE2 wird im Akuten Nierenversagen vermehrt gebildet und die Sekretion vermindert, dies führt zu einer verstärkten inflammatorischen Situation, aber im Gegenzug auch zu einer verbesserten renalen mikrovaskuläre Blutversorgung. Es wurde bei SD-Ratten eine renale Ischämie, durch Abklemmen der Arteriae renales, für 45 min operativ herbeigeführt. Die Gabe der Betablocker erfolgte nach 35min Ischämie. Nach 24h wurden Inulin- und PAH-Clearance gemessen. Die Messung der PGE2- Konzentration in Serum und Urin erfolgte mittels kompetitivem ELISA. Generell ist ein besseres renales Outcome bei den mit Nebivolol und Metoprolol Tartrat behandelten Tieren zu erkennen. Besonders ausgeprägt war dieser Effekt bei der Gruppe Cl-Nb2,5mg-Gruppe zu erkennen. Unter den Clamping-Gruppen war ebenfalls die PGE2-Claerance bei Clamp-Nb2,5mg am höchsten. Eine Korrelation zwischen erhöhter Inulinkonzentration im Urin (besseres outcome) und erhöhter PGE2- Konzentration im Urin konnte nicht nachgewiesen werden. / This study examined whether the postulated downregulation of OATs (organic anion transporters) in renal ischemic situation reduces a secretion of PGE2 and how this is related to inulin- and pah-clearance. In addition, it was analyzed if medication with the betablockers nebivolol and metoprolol tartrat has a positive effect on the renal outcome, regarding the influence on PGE2-secretion. The production of PGE2 increases in acute renal failure and its secretion is reduced, which on the one hand intensifies the inflammatory situation in the kidney, but on the other hand improves the microvascular blood support. SD-rats were subjected to bilateral renal ischemia (45min). After 35min nebivolol (2,5mg, 5mg and 10mg) or metoprolol (47,5mg) were administered. After 24h inulin- and pah-clearance were determined. PGE2 was measured in urine and serum by competitive ELISA. In general, animals receiving medication had better outcomes. This effect could be observed in the group treated with 2,5 mg nebivolol in particular. Regarding all clamp-groups, the PGE2-clearance was determined the maximum in the clamp2,5mg-group. A correlation between increased inulin-level in urine (better outcome) and increased PGE2-level in urine could not be proved.

Seit Anfang der 90-iger Jahre ist bekannt, dass nichtsteroidale Antirheumatika die Inzidenz des kolorektalen Karzinoms vermindern können. Diese antitumoröse Aktivität wird wahrscheinlich über die Cyclooxygenase-2 (COX-2) vermittelt, welche die Biosynthese von Prostaglandin H2, einer Vorstufe der Prostanoide, katalysiert. Eine Überexpression der COX-2 wurde für verschiedene Karzinome beschreiben. In dieser Studie wurde die Expression und tumorbiologische Relevanz der COX-2 im malignen Melanom, als Vertreter nichtepithelialer Tumoren, untersucht. Im Western blot wurde COX-2 Protein in den sechs untersuchten Melanomzelllinien nachgewiesen. Mittels eines spezifischen ELISAs wurde PGE2 im Überstand der Zelllinien nachgewiesen. Die PGE2-Biosynthese wurde durch den COX-2-spezifischen Inhibitor NS 398 konzentrationsabhängig inhibiert. Die IC50 der COX-2 für NS 398 wurde mit etwa 6 microM bestimmt. NS 398 inhibierte die Matrigelinvasion aller sechs Melanomzelllinien, ohne Einfluss auf die Proliferation zu haben. Die Invasionshemmung war PGE2-unabhängig, weil i) exogenes PGE2 die Invasionshemmung nicht wieder aufhob, ii) die erforderliche Konzentration von NS 398 zur Invasionshemmung im 8-fachen Bereich der IC50 der COX-2 lag. Die COX-2 ist Melanomzellen konstitutiv exprimiert und synthetisiert PGE2. NS 398 hemmt die Invasion von Melanomzellen in PGE2-unabhängiger Weise und könnte somit über ein sog. Non-COX-target wirken. / Accumulating evidence indicates that nonsteroidal anti-inflammatory drugs can reduce the incidence of colorectal cancers in humans. This antineoplastic activity is largely related to the inhibition of the inducible cyclooxygenase-2 (COX-2), which catalizes the biosynthesis of prostaglandin H2 the precursor of prostanoids. Elevated expression of COX-2 has been described in several types of epithelial tumors. In this study we evaluate the expression and function of COX-2 in malignant melanoma as a model of a non-epithelial tumor. With Western blot COX-2 protein was detected in all of six malignant melanoma cell lines. These cell lines produced prostaglandinE2 (PGE2) which was measured by a specific ELISA. PGE2 biosynthesis was blocked in a concentration dependent manner by the COX-2-specific inhibitor NS 398. The COX-2 IC50 for NS 398 was determined with 6 microM. In all six cell lines treatment with NS 398 reduced the invasion through a matrigel coated membrane while cell proliferation was not influenced. The inhibition of invasion was not mediated by PGE2, because i) exogenous PGE2 did not restore invasion, ii) the concentration needed for inhibitory effects on invasion was 8-fold higher than the IC50 of the COX-2. COX-2 is constitively expressed in malignant melanoma cells and is capable to produce PGE2. NS 398 reduces melanoma cell invsaion in a PGE2-independent manner, thus it likely further acts via a non-COX-target.

No description available.

Die Ausbildung und der Schweregrad einer Anaphylaxie kann durch verschiedene Co-Faktoren beeinflusst werden. Zu diesen zählen die nichtsteroidalen Antiphlogistika (NSAIDs), die ihre Wirkung über die Inhibition der COX entfalten. Wie NSAIDs den Schweregrad der Anaphylaxie beeinflussen, ist bisher nicht genau bekannt. Interessanterweise zeigen Anaphylaxie-Patienten mit einer NSAID-Hypersensibilität niedrige Konzentrationen des regulatorischen Prostaglandins E2 (PGE2). Zudem zeigen ASA-tolerante und –intolerante Asthma-Patienten variable anaphylaktische Sensitivitäten. Anhand der vorliegenden Arbeit sollte untersucht werden, ob sich eine PGE2-Dysregulation auf die Ausbildung und den Schweregrad der Anaphylaxie auswirkt und ob diese durch genetische Prädispositionen gefördert werden kann. Dazu wurden zunächst die PGE2 Konzentration im Serum von ANA-Patienten und gesunden Individuen gemessen. ANA-Patienten zeigten reduzierte PGE2 Level, die invers mit dem Schweregrad der ANA korrelierten. Unterstützend weisen zwei in der Allergieforschung häufig verwendete Mauslinien, Balb/c und C57BL/6, unterschiedliche PGE2 Level auf, die wiederum invers mit dem ANA-Schweregrad korrelierten. Eine Stabilisierung der PGE2 Konzentration mittels eines pharmakologischen Inhibitors der Hydroxyprostaglandin-Dehydrogenase (15-PGDH-I) in vivo führte zu einer Verbesserung des ANA Schweregrades. Um in diesem Zusammenhang den Einfluss von ASA und PGE2 besser zu verstehen, wurde das Model der systemisch passiven ANA im Mausmodel eingesetzt. ASA verschlimmerte den Schweregrad der ANA durch die Inhibition der COX1/2. PGE2 konnte diese Verschlimmerung über die EP Rezeptoren 2, 3 und 4 reduzieren. Um die zugrundeliegenden Mechanismen der Wirkweise von exogenem PGE2 und EP-Agonisten besser zu verstehen, wurden diese Zusammenhänge in murinen und humanen Mastzellen untersucht. PGE2 reduzierte die Schwere der ANA durch Inhibition der Mastzell-Aktivität in diesem System über die Rezeptoren EP2 und EP4. Anhand der vorliegenden Arbeit konnte gezeigt werden, dass bereits homöostatische PGE2 Konzentrationen die Aktivität der Mastzelle verändern und vor einer schweren ANA schützen. Zudem kann der Grad der ANA und der Einfluss des PGE2 auf die Mastzellantwort durch genetische Prädisposition beeinflusst werden. Die pharmakologische Stabilisierung des PGE2 könnte daher eine vielversprechende, therapeutische wie auch vorbeugende Strategie zur Behandlung risikoreicher ANA- Patienten sein. / The clinical outcome of anaphylaxis (ANA) can be affected by several co-factors. Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known co-factors of ANA acting via COX-inhibition. The NSAIDs-mediated mechanisms altering the severity of ANA are not well-defined. It is reported that patients of ASA (NSAID)-hypersensitivity show low levels of the regulatory prostaglandin E2 (PGE2). Moreover, the effectiveness of PGE2 administration in such patients suggests a critical role of PGE2 in ASA hypersensitivity. In addition, patients of ASA-tolerant and ASA-intolerant asthma show variable ANA sensitivities suggesting a role of genetic variation in susceptibility. The aim of this thesis was to study whether and how PGE2 dysregulation predisposes to ANA and whether genetic pre-dispositions affect the PGE2 system and therefore ANA susceptibility. First, sera from ANA patients and healthy individuals were analyzed for PGE2 levels. ANA patients were characterized by reduced PGE2 levels which inversely correlated with the severity of ANA. This disparity was confirmed by differential PGE2 levels between Balb/c and BL/6 strains, two genetic mouse strains frequently employed in allergy research. PGE2 levels in these mice were again inversely related with the severity of ANA. Results were confirmed by in vivo PGE2 stabilization using 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH-I). Pharmacological PGE2 stabilization ameliorated ANA severity in mice. A passive systemic ANA (PSA) model was applied to study the impact of ASA on ANA severity and the role of PGE2 in this context. ASA aggravated ANA by inhibiting COX-1/COX-2, while PGE2 reduced the aggravation through EP receptors 2, 3 and 4. To delineate the underlying mechanisms, murine and human mast cells were used to study the impact of exogenous PGE2 and EP agonists. PGE2 attenuated ANA severity by inhibiting MC activation through EP2 and EP4 receptors and interfering with MC signaling. In summary, this thesis demonstrates that homeostatic levels of PGE2 modulate MC activation and protect against ANA severity. The impact of PGE2 on MC responses and ANA susceptibility is governed by genetic variation. Pharmacological stabilization of PGE2 may prove to be a therapeutic or preventive strategy in the management of high-risk ANA patients.

Background: Low-grade chronic inflammation has been implicated as a risk factor in prostate-related pathologies including benign hyperplasia and cancer. Sweet cherry containing the bioactive anthocyanin (ACN), has demonstrated tumor inhibitory action in model systems, specifically inhibition of inflammatory molecules and prostaglandin biosynthesis. Objective: To assess the urinary and plasma concentrations of ACN from the daily consumption of 3 cups of sweet cherries for 4 weeks and test the relationship of ACN levels and cherry consumption to inflammatory biomarkers in an at risk population. Results: Prostaglandin E2 Metabolite (PGEM) levels were reduced with cherry consumption in men with elevated baseline values. Conclusion: We conclude that 1c (142g) of sweet cherries 3 times daily for 4 weeks significantly reduced the COX-2 metabolite, PGEM, in men with elevated baseline levels. This was the first study to examine the chronic effects of daily sweet cherries on COX-2 inhibition in an at risk population.

Os mecanismos que conferem resistência do Mycobacterium tuberculosis (Mtb) à destruição pelo hospedeiro, além da sua capacidade em permanecer e/ou multiplicar-se no interior das células fagocitárias são ainda pouco compreendidos. Nosso grupo de pesquisa tem contribuído para o entendimento do papel dos mediadores lipídicos, que incluem prostaglandinas (PGs) e leucotrienos (LTs) na tuberculose. PGs inibem a resposta imune celular TH1, a produção de citocinas e a fagocitose, e assim facilita a infecção. LTs estão envolvidos no recrutamento de leucócitos, e na modulação da síntese de citocinas, no aumento da fagocitose e dos mecanismos microbicidas, e assim contribui para a eliminação da micobactéria. Neste projeto, avaliamos in vivo e in vitro a produção dos mediadores lipídicos induzidos por cepas de Mtb isolados de pacientes com tuberculose ativa. Demonstramos neste trabalho que macrófagos alveolares infectados com os bacilos da cepa SV009 levam a maior produção de TNF- e nitrito, do que aqueles infectados com a cepa SV068. Em contraste, macrófagos alveolares infectados com os bacilos da cepa SV068 induzem a produção de muito mais LTB4, quando comparado aos bacilos da cepa SV009. Obtivemos maior recuperação de unidades formadoras de colônia (UFC) de macrófagos alveolares tratados com MK886 e infectados com bacilos da cepa SV068; enquanto que mais UFCs foram recuperadas após o tratamento com ácido caféico e infecção com a cepa SV009. Com relação a formação de corpúsculos lipídicos (CLs), observamos um maior número destes quando macrófagos alveolares foram infectados com bacilos da cepa SV068. Ainda, observamos diminuição de CLs quando tratados com MK886 ou ácido caféico. Os bacilos da cepa SV068 foram mais fagocitados, mas os macrófagos não foram muito eficazes na atividade microbicida dos mesmos. Nos experimentos in vivo vimos que camundongos balb/c infectados com a cepa SV068 morrem mais e o tratamento com MK886 parcialmente os protege e a mortalidade não está relacionada com a maior carga bacilar no pulmão ou baço. Houve aumento no recrutamento de neutrófilos induzido pela infecção especialmente após infecção com os bacilos da cepa SV068, sendo que o tratamento com MK886 inibe significativamente o recrutamento quando comparado à infecção com os bacilos da cepa SV009. Células mononucleares também foram recrutadas e permaneceram aumentadas até o final do período observado, sem muitas diferenças significativas quando comparamos a infecção com os isolados SV009 e SV068. A produção de nitrito também encontrou-se elevada em animais infectados com bacilos da cepa SV068. A análise histopatológica dos pulmões dos animais infectados mostrou intensa reação inflamatória com maior comprometimento do parênquima pulmonar dos camundongos infectados bacilos da cepa SV068, com intensa deposição de colágeno e multiplicação bacilar. Encontramos diferenças significativas em relação à producão de citocinas IL-6, IL-10, IL-1, IFN-, TNF- and IL-12 após infecção de 30 e 60 dias com as cepas SV009 e SV068. Também mostramos que há diferenças na produção de LTB4 e PGE2 após 30 e 60 dias de infecção com as cepas SV009 e SV068 em células do camundongos balb/c. Experimentos com animais 129 e 5LO-/- infectados com as duas cepas também foram realizados, e vimos que os animais 5LO-/- são mais suscetíveis à infecção especialmente quando infectados com a cepa SV068. Sugerimos que as cepas são diferentes, mas dependentes de um conjunto de fatores, e nossos dados sugerem que dentre estes mecanismos a produção de TNF- e também de mediadores lipídicos (LTB4 e PGE2) estão envolvidos. / The mechanisms that confer resistance to Mycobacterium tuberculosis (Mtb) for destruction by the host, in addition to its ability to retain and/or multiply within phagocytic cells are still poorly understood. Our research group has contributed to the understanding of the role of lipid mediators, including prostaglandins (PGs) and leukotrienes (LTs) in tuberculosis. PGs inhibit Th1 cell immune response, cytokine production and phagocytosis, thus facilitating the infection. LTs are involved in the leukocytes recruitment, and modulation of cytokine synthesis, phagocytosis and microbicidal mechanisms enhancement, and contribute to the elimination of the mycobacteria. In this project, we evaluated in vivo and in vitro the lipid mediators production induced by Mtb strains isolated from patients with active tuberculosis. We demonstrated in this study that alveolar macrophages infected with bacilli from SV009 strain lead to an increase of TNF- production and nitrite, than those infected with the strain SV068. In contrast, alveolar macrophages infected with bacilli from SV068 strain induced more LTB4 production when compared to SV009 infection. We obtained higher recovery colony forming units (CFU) of alveolar macrophages treated with MK886 and infected with bacilli from SV068 strain; while more CFUs were recovered after treatment with caffeic acid and infection with bacilli from SV009 strain. Regarding the lipid bodies (LBs) formation, we observed a greater number of these structures, when alveolar macrophages were infected with bacilli from SV068 strain. Still, we observed a decrease of LBs when the macrophages were treated with MK886 and caffeic acid. Bacilli from SV068 strain were more phagocytosed, but macrophages were not very effective in the microbicidal activity. In the in vivo experiments we found that mice infected with SV068 strain die more than the other and MK886 treatment partially protects the mice, besides, the mortality is not related to the higher bacterial load in the lung or spleen. There was an increase in neutrophil recruitment induced after infection, especially after infection with SV068 strain, and treatment with MK886 significantly inhibits recruitment when compared to infection with SV009 strain. Mononuclear cells were also recruited and remained increased until the end of the observed period, without many significant differences when comparing infection with SV009 and SV068 strains. The nitrite production was also found greater in animals infected with bacilli from SV068 strain. Histopathological analysis of the infected mice lungs showed an intense inflammatory reaction with greater impairment of the mice lungs when infected with bacilli from SV068 strain with an intense collagen deposition and multiplication of bacilli. We suggest that the SV068 strain is more virulent and participates of the immune response by lipid mediators dependent mechanisms.