Of all of the cancer patients throughout the world, approximately 50% of them are affected to some degree by cachexia. This syndrome involves significant skeletal muscle wasting, loss of adipose tissue and overall decrease in body weight in patients, particularly those with lung, pancreatic and gastric cancers. Cancer-induced cachexia is characterized by the presence of increased cytokines, notably TNF-α, IL-1β and IL-6. Most patients suffering of cancer-induced cachexia experience increased toxicity in response to chemotherapy, leading to fewer rounds of treatment and thus impeding the patients’ chances for recovery. More research into effective treatments for cancer-induced cachexia would therefore be indispensable. The inhibitor of apoptosis proteins (IAPs) have emerged as important cancer targets, primarily because of their roles as caspase inhibitors and regulators of NF-κB signalling. Small molecule IAP antagonists known as Smac mimetic compounds (SMCs) are currently in stage I/II clinical trials. They function by targeting cIAP1 and cIAP2 (and to a lesser extent, XIAP) resulting in a cytokine mediated death response in cancer cells. SMCs induce the production of TNF-α, a cytokine with which SMCs can potently synergize. However, limited efficacy occurs in some cancer cell lines (presumably because TNF-α cannot be induced in an autocrine fashion) and an exogenous source of the cytokine, such as that induced by using an oncolytic virus, is required. Notably, TNF-α (initially known as “cachectin”) is known to play a significant role in the induction of skeletal muscle atrophy. We therefore wanted to examine the effects of TNF-α induction by SMC and oncolytic virus co-treatment on both tumour regression and skeletal muscle in tumour bearing mice. We investigated the effects of SMC treatment on Lewis Lung Carcinoma (LLC) and B16F10 melanoma cell lines, both of which have been shown to be established cachectic cancer cell lines. Our in-vitro analysis of LLC and B16F10 cells revealed that LLC cells are sensitive to SMC and TNF-α co-treatment whereas B16F10 cancer cells remain resistant. SMC treatment, in combination with an oncolytic virus, VSVΔ51, increased tumour regression and survival time in LLC tumour bearing mice. Based on findings from previous studies, we investigated the role of cellular FLICE-like inhibitory protein (c-FLIP) in the resistance of the B16F10 melanoma cell line to SMC treatment. We were able to determine that the down-regulation of c-FLIP sensitizes the B16F10 cells to SMC and TNF-α induced cell death. In extending these findings, we found that SMC treatment alone can cause skeletal muscle wasting in the tibialis anterior muscle of LLC tumour bearing mice. However, the atrophic response was observed to be minimal as documented by a slight but significant decrease (approximately 10%) in muscle fibre cross-sectional area. Moreover, no biochemical evidence of muscle atrophy, as visualized by changes in the expression of myosin heavy chain (MHC) and Muscle RING Finger protein 1 (MuRF1), was found. Regardless, we speculate that the impact of SMC treatment on muscle wasting would be transient and reversible, and propose that the benefits of such a combination immunotherapy would greatly outweigh the risks.

Die vorliegende publikationsbasierte Dissertationsschrift erörtert auf der Basis experimenteller Untersuchungen im Tiermodell die Auswirkungen von Stress auf die Zytokinproduktion und depressionsähnliches Verhalten. Außerdem wird getestet, ob die Blockade des Zytokins Tumornekrosefaktor-α (TNF‑α) eine Möglichkeit zur antidepressiven Intervention darstellt. Einleitend werden die Zusammenhänge von Stress, Zytokinen und Depression referiert sowie das hypothetische Modell erläutert, das den publizierten Untersuchungen zugrunde liegt. Es wird hypothetisiert, dass Stress zur Erhöhung der Produktion proinflammatorischer Zytokine führt und dass die vermehrte Zytokinproduktion depressive Verhaltensweisen hervorruft. Aus dieser Annahme leitet sich die Möglichkeit ab, durch Blockade der Wirkung des proinflammatorischen Zytokins TNF‑α antidepressive Effekte zu erzielen. In den beiden Arbeiten „The impact of social isolation on immunological parameters in rats“ (Archives of Toxicology) und „Stress-induced cytokine changes in rats“ (European Cytokine Network) wurde der Einfluss von sozialer Isolation, chronischem, milden und akutem Stress auf die Zytokinproduktion untersucht. In diesen Untersuchungen führten die verschiedenen Stressarten zu einer Modulation der Produktion proinflammatorischer Zytokine. Die dritte Publikation „Antidepressant effects of TNF‑α blockade in an animal model of depression“ (Journal of Psychiatric Research) berichtet von einem Experiment, in dem untersucht wurde, ob der TNF‑α-Inhibitor Etanercept antidepressive Effekte aufweist. Tatsächlich zeigte sich unter Etanercept ein Rückgang des depressionsähnlichen Verhaltens im forced swim test (FST) analog zu Verhaltensänderungen durch das in Tierversuchen als Standard-Antidepressivum geltende Imipramin. Die Autoren schlussfolgern, dass das Zytokinsystem durch Stress moduliert wird und so in die pathophysiologische Entwicklung einer Depression involviert sein könnte. Zytokininhibitoren könnten eine neue Klasse der Antidepressiva bei Therapieresistenz werden, wenn sich die Ergebnisse dieser Tierversuche in Studien an Probanden und an Patienten replizieren lassen.:Abkürzungsverzeichnis 5 1. Einführung 6 1.1. Zytokine 6 1.1.1. Tumornekrosefaktor-α 7 1.1.2. Interleukin‑1β 9 1.1.3. Interleukin‑2 9 1.1.4. Interleukin‑4 10 1.1.5. Interleukin‑6 10 1.1.6. Interleukin‑10 10 1.1.7. Interleukin‑17 11 1.1.8. Interleukin‑22 11 1.1.9. Interferon‑γ 12 1.2. Stress 12 1.2.1. Sympathikus und Zytokine 12 1.2.2. Hypothalamus-Hypophysen-Nebennieren-Achse und Zytokine 12 1.3. Stress und Immunsystem 13 1.4. Stressarten und ihre Paradigmen im Tierversuch 14 1.4.1. Stress durch Isolation bei Ratten 14 1.4.2. Forced Swim Test: Paradigma zur Messung depressionsähnlichen Verhaltens und Modell für akuten Stress 15 1.4.3. Restraint Stress 16 1.5. Depression und Stress 16 1.6. Depression und Entzündung 17 1.7. Neue Therapieansätze gegen Depression 18 1.8. Theoretisches Modell und Fragestellung 19 1.9. Bibliografie zur Einführung 20 2. Originalarbeiten 34 „The impact of social isolation on immunological parameters in rats“ 35 „Stress-induced cytokine changes in rats“ 38 „Antidepressant effects of TNF-α blockade in an animal model of depression“ 45 3. Zusammenfassung 51 4. Anhang 55 Erklärung über die selbständige Abfassung der Arbeit 55 Lebenslauf 56 Publikationen 57 Danksagung 58

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Depression and other mental disorders are the leading cause of disability worldwide and their burden has increased considerably over past decades. However, advances in psychopharmacology of psychiatric disorders are not in measure with this negativ trend. As a result, a large body of researchinpsychiatryandneurosciencestries to furtherourunderstanding of pathophysiologicalmechanismsunderlyingmooddisorders andothermentalillnesses in order to improve the efficacy of current treatments and to identify new therapeutic agents. According to current evidence, stress-related pathways and inflammation processes are directly involved in thedevelopment of depressive disorder andseveral other psychiatric conditions.Thestudy of the effects and consequences of stress exposure requires an interdisciplinary approach,taking into account specific aspects of the "inputs", such as chronic stress and traumatic experiences, and related psychological processes, with the crucial role of dissociation. Following these theoretical findings, the empirical research performed in two cohorts of inpatients with depressive disorder focused on immune and endocrine responses to stress and their relationship to psychopathological symptoms, specifically trauma-related symptoms, psychic and somatoform dissociation and depressive...

Tim-3 has been linked to several inflammatory diseases by regulation on both adaptive and innate immunities. Here, we assessed the augmented expression of Tim-3 in brain tissue of ischemia-reperfusion mice and PBMCs of ischemic stroke (IS) patients. The augmented expression of Tim-3 significantly correlated with abnormal lipid levels. In vitro studies showed that plasma from ischemic stroke patients induced Tim-3 expression in THP- 1 cells. More importantly, our results revealed a significant correlation of Tim-3 expression on CD4 + T cells with systemic IL-17 in patients with ischemic stroke. Consistently, we also found a positive correlation of Tim-3 expression on CD14 + monocytes and serum TNF-a in IS patients. Collectively, augmented expression of Tim-3 may play an important role in the pathogenesis of ischemic stroke by regulation of proinflammatory cytokines. Further studies will give us new insights on the pathogenesis of ischemic stroke and potentially provide a new target at the medical therapy.

Dietary vitamin E, highly expressed in palm oil, exists as either tocopherols or tocotrienols. Evidence indicates that vitamin Es maybe potent cancer preventive agents. In this study, the y- and O- isoforms of vitamin E were found to he the most effective at cancer cell growth inhibition, with the tocotrienols being more effective than the tocopherols in androgen-independent PC-3 prostate cancer cells. To assure that these compounds were selective toward cancer cells, the growth arrest of PrEC normal prostate cells was compared to PC-3 cells. At concentrations of -30 iM dietary, y-vitamin Es showed no signficant growth arrest on PrEC cell growth, hut selectively inhibited growth in the PC-3 cancer cells. Moreover y-Tocotrienol demonstrated a greater potential to inhibit growth in cancer cells at these lower concentrations than did y-Tocopherol. Two independent pathways important in carcinogenesis were tested: PPAR y and NFicB. The PPAR y was up regulated by both dietary y-vitamin Es by the modulation of the endogenous ligand 15-S-HETE, while NFicB was only regulated by y-Tocotrienol. The modulation of NFicB was confirmed by the down regulation of the pro-Apoptotic proteins clAP, xIAP, and BcL-2 which potentiate apoptosis and are down stream effectors of NFicB.

Journal of Investigative Dermatology (2015) 135, 1007–1015; doi:10.1038/jid.2014.516; published online 8 January 2015 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18890号 / 医博第4001号 / 新制||医||1009(附属図書館) / 31841 / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 髙折 晃史, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18892号 / 医博第4003号 / 新制||医||1009(附属図書館) / 31843 / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 鈴木 茂彦, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20667号 / 医博第4277号 / 新制||医||1024(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 妹尾 浩, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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