Fragestellung: Wir gingen der Frage nach, inwieweit genetische Variationen im Gen für den Tumor Nekrose Faktor-alpha einen Einfluß auf die Krankheitsprogression oder die Entstehung bzw. Ausprägung HIV-assoziierter Erkrankungen haben. Methoden: Die Promotorregion sowie die kodierenden Sequenzen des TNF-alpha-Gens wurden mittels SSCP-Analyse auf genetische Variationen untersucht. Anschließend erfolgte die Charakterisierung der häufigsten bekannten Promotorpolymorphismen mittels Restriktionsfragment-Längenpolymorphismus-Analyse (RFLP). Die Bestätigung der Polymorphismen der RFLP-Analyse erfolgte an ausgewählten Proben durch DNA-Fluoreszenzsequenzierung. In sämtlichen Fällen handelte es sich um singuläre Basentransitionen von Guanin zu Adenin. Ergebnisse: Unter Einbeziehung verschiedener Progressionsparameter wie der CD4-Zellzahl, des Zeitraumes vom ARC-Stadium zum AIDS-Stadium und AIDS-assoziierter Krankheiten wie dem Wasting Syndrom und der HIV-Enzephalopathie, erfolgte anschließend die statistische Analyse in Korrelation mit den ermittelten Genotypen. Es zeigte sich bei keiner der statistischen Analysen eine signifikante Assoziation mit einem bestimmten TNF-alpha-Genotyp. Schlußfolgerung: Es ist kritisch anzumerken, daß für einige Subanalysen die Größe der untersuchten Patientengruppe zu gering war, um eine statistische Aussagekraft für seltene Allele zu erreichen. Anhand der hier vorgelegten Ergebnisse hat der TNF-alpha-Genotyp weder einen Einfluß auf die Progression der HIV-Erkrankung noch auf die Ausbildung HIV-assoziierter Erkrankungen wie dem Wasting Syndrom oder der HIV-Enzephalopathie. / Objective: We determined whether variation of the tumor necrosis factor-alpha gene had an impact on HIV disease progression or the prevalence of hiv-associated diseases. Methods: The promotor region of the TNF-alpha gene were examined with SSCP analysis for polymorphisms in the promotor region. The most common promotor polymorphisms were characterized with restriction fragment length polymorphism analysis (RFLP). To confirm RFLP results DNA fluorescence sequenzing analyses were performed with selected samples. In all cases with diagnosis of promotor polymorphisms single base transitions from guanine to adenine were confirmed. Results: Statistical analyses correlated the genotypes with different markers for disease progression e.g. CD4-count, the period from ARC to AIDS and the occurance of HIV associated diseases (wasting syndrome, hiv encephalopathy). In none of the statistical analyses significant association with a certain TNF-alpha genotyp could be demonstrated. Conclusion: For some subanalysis the sample sizes were too small in order to be able to make safe statistical statements concerning rare allels. Regarding our results, none of the examined tumor necrosis factor-alpha promotor polymorphisms had an impact on HIV disease progression or the prevalence of hiv-associated diseases.

Die kontinuierliche Rezirkulation von Immunzellen durch periphere und sekundäre lymphatische Organe (SLOs) ist Bestandteil der Immunüberwachung und wichtig für die Aufrechterhaltung und Funktionsbereitschaft des Immunsystems. Der homöostatische Chemokinrezeptor CCR7 vermittelt dabei nicht nur die Rezirkulation von Lymphozyten durch SLOs, sondern scheint auch an der homöostatischen Rezirkulation von Lymphozyten durch nicht-lymphoide periphere Gewebe beteiligt zu sein. Im Rahmen dieser Arbeit wurde mithilfe von CCR7-defizienten Mäusen die funktionale Bedeutung von CCR7 für die homöostatische Rezirkulation von Lymphozyten durch das Peritoneum untersucht und nachgewiesen, dass CCR7 der dominante Chemokinrezeptor ist, der unter physiologischen Bedingungen die Transitzeit von Lymphozyten durch das Peritoneum festlegt. Die gestörte Rezirkulation von Lymphozyten begünstigte außerdem die Entstehung von tertiären lymphoiden Organen (TLOs) in der Magenschleimhaut von CCR7-defizienten Mäusen. Untersuchungen zur zellulären und molekularen Grundlage dieser und weiterer pathomorphologischer Veränderungen in der Magenschleimhaut von CCR7-defizienten Mäusen verdeutlichten die Funktion von CCR7 für die Etablierung von zentraler und peripherer Toleranz gegenüber gastrischen Antigenen. Fehlt CCR7, dann entwickelten Mäuse eine spontane Autoimmungastritis, welche durch gastritogene CD4+ T-Zellen verursacht wurde, deren Aktivierung auch unabhängig von Lymphknoten und TLOs erfolgte. Die Entstehung von TLOs wird auch bei einer durch Helicobacter pylori ausgelösten chronischen Gastritis beobachtet. Die Expression des homöostatischen Chemokinrezeptors CXCR5 und seines Liganden CXCL13 ist mit der Entwicklung dieser TLOs korreliert worden. Unter Verwendung eines Mausmodells für H. pylori-induzierte chronische Gastritis konnte gezeigt werden, dass CXCR5 die Ausbildung von TLOs vermittelt und eine Rolle für die Induktion von H. pylori-spezifischen T-Zell- sowie humoralen Immunantworten spielt. / Homeostatic recirculation of immune cells through peripheral and secondary lympoid organs (SLOs) is required for immune surveillance and the maintenance and functionality of the immune system. The homeostatic chemokine receptor CCR7 controls not only lymphoid cell trafficking to and within SLOs, but also seems to be involved in the homeostatic recirculation of lymphocytes through non-lymphoid peripheral tissues. Within the scope of this work we investigated the functional relevance of CCR7 for the homeostatic recirculation of lymphocytes through the peritoneal cavity and could show, that CCR7 is the dominant chemokine receptor which defines the transit time of lymphocytes in the peritoneal cavity under physiological conditions. Impaired recirculation of lymphocytes also promoted the development of tertiary lymphoid organs (TLOs) in the gastric mucosa of CCR7-deficient mice. Analysis of the cellular and molecular mechanisms underlying these and other pathomorphological alterations in the gastric mucosa of CCR7-deficient mice provided further evidence regarding the function of CCR7 for the establishment of central and peripheral tolerance towards gastric antigens. Mice that lack CCR7 spontaneously developed autoimmune gastritis, which was caused by gastritogenic CD4+ T-cells. Such autoreactive T cell responses were also initiated in the absence of lymph nodes and TLOs in CCR7/LT-alpha double-deficient mice. Development of TLOs is also observed during chronic gastritis induced by Helicobacter pylori. The expression of the homeostatic chemokine receptor CXCR5 and its ligand CXCL13 has been correlated with the development of these TLOs. Using a mouse model for H. pylori-induced chronic gastritis, we could show that CXCR5 is responsible for the development of TLOs and also plays a role for the induction of H. pylori-specific T and B cell responses.

ALS is an often lethal disease involving degeneration of motor neurons in the brain and spinal cord. Current treatments only extend life by several months, and novel therapies are needed. We combined RNA-Sequencing, systems biology analyses, and molecular biology assays to elucidate sporadic ALS group-specific differences in postmortem cervical spinal sections (7 sALS and 8 control samples) that may be relevant to disease pathology. >55 million 2X150 RNA-sequencing reads per sample were generated and processed. In Chapter 2, we used bioinformatics tools to identify nuclear differentially expressed genes (DEGs) between our two groups. Further, we used Weighted Gene Co-Expression Network Analysis to identify gene co-expression networks associated with disease status. Qiagen’s Ingenuity Pathway Analysis revealed our sALS group-specific DEGs and a sALS group-specific gene co-expression network were associated with inflammatory processes and TNF-α signaling. Further, TNFAIP2 was identified as a sALS group-specific upregulated DEG and a network hub gene within that network. We hypothesized TNFAIP2’s upregulation in our ALS samples reflected increased TNF-α signaling and that TNFAIP2 promoted motor neuron death via TNF superfamily apoptotic pathways. Transient overexpression of TNFAIP2 decreased cell viability in both neural stem cells and induced pluripotent stem cell-derived motor neurons. Further, inhibition of activated caspase 9 (a protein necessary for TNF superfamily mitochondrial-mediated apoptosis) reversed this effect in neural stem cells. In Chapters 3 and 4, we used bioinformatics tools to identify sALS group-specifc mitochondrial DEGs and differentially used exons (DUEs). Qiagen’s Ingenuity Pathway Analysis revealed our sALS group-specific DUEs were associated with cholesterol biosynthesis.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Objetivo: Avaliar o perfil de citocinas pró-inflamatórias e de melatonina no cordão umbilical e no sangue materno de gestantes hígidas de acordo com a via de parto. Métodos: Entre março e setembro de 2010, foi realizado estudo observacional prospectivo no Hospital Universitário da Universidade de São Paulo. Foram dosadas citocinas (IL-1, IL-6, TNF) e melatonina em pacientes sem doenças clínicas ou complicações obstétricas que entraram em trabalho de parto espontâneo. As concentrações de citocinas e de melatonina foram comparadas de acordo com a via de parto, além do período do dia e do local de coleta. O sangue retirado da veia do cordão umbilical (VCU) era obtido imediatamente após o parto, sendo que após uma hora era colhido o sangue da veia braquial materna (VB). Foram excluídas pacientes com infecção, parto prematuro e sofrimento fetal. Resultados: Foram estudadas 50 parturientes, das quais 25 evoluíram para parto vaginal e 25 para cesárea. A idade materna foi em média 26,0 ± 6,7 anos. A idade gestacional no parto foi em média 39,5 ± 1,7 semanas. O peso médio dos recém-nascidos foi 3366,5 ± 340,2 gramas. Todos os casos receberam analgesia durante o parto (analgesia combinada: peridural e raquianestesia). A maioria das pacientes era de nulíparas (31/50 - 62,0%). A duração do trabalho de parto foi semelhante nas pacientes que evoluíram para o parto vaginal (7,6 ± 4,4 horas) e nas que foram submetidas à operação cesariana (8,2 ± 4,4 horas; p=0,87). Houve tendência de níveis mais elevados de melatonina no VCU e na VB em pacientes após parto vaginal, porém sem diferença estatística (p=0,41 e p=0,16). Pacientes que evoluíram para cesariana apresentaram dosagens significativamente maiores de TNF na VB, de IL-1 na VCU e na VB e de IL-6 na VCU que em pacientes que evoluíram para parto vaginal (p= 0,02; p<0,01; p<0,01 e p<0,01; respectivamente). Observou-se variação no ritmo circadiano das dosagens dessas citocinas após cesariana, com correlação significativa entre dosagem de melatonina e de citocinas nessa via de parto. Conclusão: Pacientes submetidas à operação cesariana apresentaram tendência a redução da secreção de melatonina, com aumento significativo da secreção de citocinas pró-inflamatórias, o que pode ser conseqüência do processo inflamatório relacionado ao estresse cirúrgico / Objetive: To evaluate the profile of pro-inflammatory cytokines and the melatonin level in maternal and umbilical cord blood samples in accordance with the mode of delivery. Methods: Between March 2010 and September 2010, a prospective observational study was conducted at University Hospital of University of São Paulo. Cytokines (IL-1, IL-6, TNF) and melatonin levels were analyzed from maternal brachial vein (BV) and umbilical cord vein (UCV) obtained from healthy patients that started spontaneous labor. The levels of cytokines and melatonin were evaluated in accordance to the mode of delivery as well as the day period and the local of blood sample (UCV - immediately after delivery and BV - one hour after delivery). Patients with infection, preterm labor and fetal distress were excluded. Results: A total of 50 patients were evaluated in the present study: 25 underwent vaginal delivery and 25 c-section. Mean maternal age was 26.0 ± 6.7 years. Mean gestational age at delivery was 39.5 ± 1.7 weeks. The average of newborn weight was 3366.5 ± 340.2 grams. All patients had combined epidural and raquianesthesia. The majority of the patients was nullipara (31/50 62.0%). The labor duration was similar in patients that underwent vaginal delivery (7.6 ± 4.4 hours) or c-section (8.2 ± 4.4 hours, p=0.87). There was a tendency of increased levels of melatonin in the UCV and BV samples after vaginal deliveries, but with statistical significance (p=0.41 and p=0.16). Patients that underwent c-section had increased levels of TNF at the BV, IL-1 at the UCV and BV and IL-6 at the UCV than in patients that underwent vaginal delivery (p= 0.02; p<0.01; p<0.01 and p<0.01; respectively). Circadian variations of the cytokines and the melatonin levels were observed in patients that underwent c-section, with significant correlation between the levels of cytokines and melatonin. Conclusion: Patients that underwent c-section had a tendency of reduced melatonin level, with significant increase in the cytokine levels, which may be consequent of the inflammatory process related to the surgical stress.

TRAIL has been widely investigated as an anti-cancer agent due to its high efficacy in vitro and its safety to normal cells. However, TRAIL-based agents only showed modest effect in clinical studies because of TRAIL resistance. In addition to apoptosis, TRAIL has also been reported to promote pro-survival signalings, cell migration and metastasis. One of the current strategies in the development of TRAIL-based therapeutics focuses on the search of sensitizing agents that help overcome TRAIL resistance without increasing harm to normal cells. / This study reports a novel combination of TRAIL and 4-methylumbelliferone (4-MU) which can kill HeLa cells and HepG2 cells synergistically without cytotoxicity to Hs68 non-tumorigenic cells. This combination also effectively inhibited cancer cell proliferation and potentiated apoptosis by accumulation of tBid, down-regulation of anti-apoptotic proteins and inhibition of Akt. More importantly, 4-MU could suppress the recovery of HeLa cells from TRAIL-induced apoptosis, a process previously implicated to be associated with cancer relapse and tumor heterogeneity. This study has provided solid evidences substantiating further research on TRAIL-4-MU combination. / 腫瘤壞死因子相關凋亡誘導配體 (TRAIL) 在體外實驗中有良好抗癌作用，且不會傷害正常細胞，使之得到廣泛研究，成為近年熱門的新抗癌分子。然而TRAIL 在臨床實驗中並沒有顯著抗癌功效，一般認為人體腫瘤細胞對TRAIL 具有耐藥性。研究文獻亦指出，除了細胞凋亡外，TRAIL亦會誘發細胞存活機制、促進細胞移行及癌細胞轉移。目前，對於TRAIL相關藥品抗癌作用的研究有幾個大方向，其中之一就是尋找良好的增敏分子。良好的增敏分子應能夠增力癌細胞對TRAIL的敏感性，對抗癌細胞對TRAIL的耐藥性，同時不能殺傷正常細胞。 / 本研究揭示了一個全新的抗癌藥物聯合。當TRAIL聯合4-甲基伞形酮(4-MU)能產生協同作用，殺傷HeLa癌細胞和HepG2癌細胞而不會傷害Hs68正常細胞。此組合能有效抑制癌細胞生長，並透過增加tBid蛋白表達、減少抗凋亡蛋白表達及抑制Akt來促進細胞凋亡。更為重要的是，4-MU能抑制HeLa癌細胞自TRAIL誘導凋亡的恢復和逆轉。而癌細胞凋亡逆轉一般被視為與癌症復發及腫瘤多樣性有關。本研究提供了實質證據，支持對TRAIL-4-MU組合的後續研究。 / Wu, Hoi Yan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 90-107). / Abstracts also in Chinese. / Title from PDF title page (viewed on 05, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Les stratégies de traitement biologiques ciblant le TNF-α se sont avérées efficaces pour réduire l'inflammation et les symptômes cliniques dans plusieurs maladies inflammatoires chroniques et sont maintenant couramment utilisées pour les patients qui ne répondent pas aux AINS au cours de la spondyloarthrite (SpA). Cependant, 30 à 40% des patients ne répondent pas aux anti-TNF, et il est actuellement impossible de prédire la réponse des patients à ces biomédicaments. Pour améliorer les résultats cliniques, nous avons besoin d’une part d’une meilleure compréhension des mécanismes d’action des anti-TNF sur le système immunitaire, et d’autre part de biomarqueurs permettant de prédire la réponse à ces biomédicaments afin de guider la décision thérapeutique. Mon projet de doctorat a porté sur deux objectifs complémentaires: (i) l'objectif principal était de progresser dans notre compréhension des mécanismes pathogéniques impliqués dans la SpA axiale et de définir de quelle façon les anti-TNF-α affectent les réponses immunitaires des patients, (ii) de développer des biomarqueurs pour prédire la réponse thérapeutique aux inhibiteurs du TNF. En collaboration avec l'équipe du Pr. Dougados à l'Hôpital Cochin, nous avons recruté deux cohortes indépendantes de patients SpA ayant une maladie active et pour lesquels nous avons collecté des échantillons de sang avant l'initiation du traitement par anti-TNF puis 1 semaine et 3 mois après le début du traitement. Les réponses immunitaires de ces patients ont été analysées à l'aide de tests hautement standardisés réalisés ex-vivo sur sang circulant. Ces tests "TruCulture" se présentent sous forme de seringues, dans lesquelles 1 ml de sang total est mis à incuber avec un stimulus spécifique ; 20 stimuli différents ont été testé et validé avant et après traitement dans les deux cohortes de patients. Nous avons observé une réduction très significative de la sécrétion de IL-1ra, IL-1β, IL-8, and MIP-1β en réponse à des stimuli microbiens et à des agonistes des TLR dans les échantillons de sang prélevés 7 jours et/ou 3 mois après le début du traitement. Pour identifier les bases moléculaires de l’action des inhibiteurs du TNF nous avons analysé l'expression des gènes dans ces différentes conditions de stimulation. L'analyse bioinformatique quantitative de l'expression des gènes (QuSAGE) a révélé que les gènes les plus modulés par le traitement anti-TNF étaient NF-KB et les gènes cibles de NF-kB, y compris le TNF lui-même et l’IL1B. Nos données suggèrent que les inhibiteurs du TNF agissent principalement en perturbant une boucle autorégulatrice pilotée par NF-kB. Afin d'identifier les signatures immunologiques de réponse aux anti-TNF avant le début du traitement, nous avons corrélé les réponses immunitaires chez les patients analysés au temps 0 à la réponse thérapeutique aux anti-TNF mesurée à 3 mois. Nos résultats suggèrent que les patients atteints de SpA et exprimant des niveaux inférieurs de PAX5 et des niveaux supérieurs de SPP1 en réponse à la stimulation avec SEB avant l'initiation de la thérapie anti-TNF ont les meilleures réponses thérapeutiques. Notre recherche montre que les tests TruCulture sont un outil efficace pour étudier les fonctions immunitaires chez les patients atteints de SpA et que les effets du traitement anti-TNF peuvent être mesurés lorsque les cellules immunitaires sont stimulées. En terme de recherche translationnelle, nous avons identifié des molécules qui pourront être utilisés comme biomarqueurs pour aider les cliniciens à prédire les réponses thérapeutiques aux traitements anti TNF / The introduction of anti-TNF therapy has proven effective to reduce inflammation and clinical symptoms in several chronic inflammatory diseases. However, 30-40% of patients do not respond to TNF blockers and it is currently not possible to predict responsiveness of patients to anti-TNF therapy. Furthermore, their impact on the immune system is incompletely understood. The goals of my PhD project were (i) to define the impact of anti-TNF therapy on immune responses to microbial challenges and stimuli targeting specific immune pathways in spondyloarthritis (SpA) patients, and (ii) to identify immunological correlates associated with therapeutic responses to TNF-blockers.Using a set of whole-blood, syringe-based assays to perform ex vivo stimulation while preserving physiological cellular interactions (TruCulture assays), we have performed a pilot study in SpA patients and investigated immune responses to 20 different stimuli before and 3 months after initiation of anti-TNF therapy. These findings were validated in a replication cohort, also assessing the effects of anti-TNF agents after only one week of treatment. We observed a highly significant reduction of the secretion of IL-1ra, IL-1β, IL-8 and MIP-1β in response to selected stimuli after 3 months of treatment compared to the baseline. Interestingly, these changes were already detectable after a single injection of an anti-TNF agent. To gain insight into the molecular mechanism of TNF blockers, we profiled gene expression in the stimulation cultures from all patients. Quantitative set analysis for gene expression (QuSAGE) revealed that the gene modules most affected by anti-TNF therapy are NF-kB transcription factors and inhibitors and NF-kB target genes, including TNF itself and IL1B. Our data suggest that TNF-blockers primarily act by disrupting an autoregulatory loop driven by NF-kB. We also tested whether there is a correlation between the responses of immune cells to specific stimuli and the clinical response to TNF-blockers. The decision tree model that we trained and validated suggests that SpA patients who expressed lower levels of PAX5 and higher levels of SPP1 in response to SEB stimulation before initiation of anti-TNF therapy had the best therapeutic responses. Our study shows that TruCulture assays are an efficient and robust tool to monitor immune functions in SpA patients and that the effects of anti-TNF therapy can be measured when immune cells are challenged, but not at steady state. Our data also indicate that analyzing immune responses in patients before therapy is a promising strategy to develop biomarkers for prediction of therapeutic responses to TNF-blockers

Objetivo: Avaliar o perfil de citocinas pró-inflamatórias e de melatonina no cordão umbilical e no sangue materno de gestantes hígidas de acordo com a via de parto. Métodos: Entre março e setembro de 2010, foi realizado estudo observacional prospectivo no Hospital Universitário da Universidade de São Paulo. Foram dosadas citocinas (IL-1, IL-6, TNF) e melatonina em pacientes sem doenças clínicas ou complicações obstétricas que entraram em trabalho de parto espontâneo. As concentrações de citocinas e de melatonina foram comparadas de acordo com a via de parto, além do período do dia e do local de coleta. O sangue retirado da veia do cordão umbilical (VCU) era obtido imediatamente após o parto, sendo que após uma hora era colhido o sangue da veia braquial materna (VB). Foram excluídas pacientes com infecção, parto prematuro e sofrimento fetal. Resultados: Foram estudadas 50 parturientes, das quais 25 evoluíram para parto vaginal e 25 para cesárea. A idade materna foi em média 26,0 ± 6,7 anos. A idade gestacional no parto foi em média 39,5 ± 1,7 semanas. O peso médio dos recém-nascidos foi 3366,5 ± 340,2 gramas. Todos os casos receberam analgesia durante o parto (analgesia combinada: peridural e raquianestesia). A maioria das pacientes era de nulíparas (31/50 - 62,0%). A duração do trabalho de parto foi semelhante nas pacientes que evoluíram para o parto vaginal (7,6 ± 4,4 horas) e nas que foram submetidas à operação cesariana (8,2 ± 4,4 horas; p=0,87). Houve tendência de níveis mais elevados de melatonina no VCU e na VB em pacientes após parto vaginal, porém sem diferença estatística (p=0,41 e p=0,16). Pacientes que evoluíram para cesariana apresentaram dosagens significativamente maiores de TNF na VB, de IL-1 na VCU e na VB e de IL-6 na VCU que em pacientes que evoluíram para parto vaginal (p= 0,02; p<0,01; p<0,01 e p<0,01; respectivamente). Observou-se variação no ritmo circadiano das dosagens dessas citocinas após cesariana, com correlação significativa entre dosagem de melatonina e de citocinas nessa via de parto. Conclusão: Pacientes submetidas à operação cesariana apresentaram tendência a redução da secreção de melatonina, com aumento significativo da secreção de citocinas pró-inflamatórias, o que pode ser conseqüência do processo inflamatório relacionado ao estresse cirúrgico / Objetive: To evaluate the profile of pro-inflammatory cytokines and the melatonin level in maternal and umbilical cord blood samples in accordance with the mode of delivery. Methods: Between March 2010 and September 2010, a prospective observational study was conducted at University Hospital of University of São Paulo. Cytokines (IL-1, IL-6, TNF) and melatonin levels were analyzed from maternal brachial vein (BV) and umbilical cord vein (UCV) obtained from healthy patients that started spontaneous labor. The levels of cytokines and melatonin were evaluated in accordance to the mode of delivery as well as the day period and the local of blood sample (UCV - immediately after delivery and BV - one hour after delivery). Patients with infection, preterm labor and fetal distress were excluded. Results: A total of 50 patients were evaluated in the present study: 25 underwent vaginal delivery and 25 c-section. Mean maternal age was 26.0 ± 6.7 years. Mean gestational age at delivery was 39.5 ± 1.7 weeks. The average of newborn weight was 3366.5 ± 340.2 grams. All patients had combined epidural and raquianesthesia. The majority of the patients was nullipara (31/50 62.0%). The labor duration was similar in patients that underwent vaginal delivery (7.6 ± 4.4 hours) or c-section (8.2 ± 4.4 hours, p=0.87). There was a tendency of increased levels of melatonin in the UCV and BV samples after vaginal deliveries, but with statistical significance (p=0.41 and p=0.16). Patients that underwent c-section had increased levels of TNF at the BV, IL-1 at the UCV and BV and IL-6 at the UCV than in patients that underwent vaginal delivery (p= 0.02; p<0.01; p<0.01 and p<0.01; respectively). Circadian variations of the cytokines and the melatonin levels were observed in patients that underwent c-section, with significant correlation between the levels of cytokines and melatonin. Conclusion: Patients that underwent c-section had a tendency of reduced melatonin level, with significant increase in the cytokine levels, which may be consequent of the inflammatory process related to the surgical stress.