Adrenal gland insufficiency – the clinical manifestation of deficient production or action of adrenal steroids – is a life-threatening disorder. Among many factors which can predispose to primary adrenal failure, an autoimmune adrenalitis and infectious agents play a major role. The initial host defense against bacterial infections is executed primarily by the pattern recognition receptors, e.g. Toll-like receptors (TLRs), expressed in cells from the innate immune system. Upon activation, TLRs have been found to regulate various levels of innate and adaptive immunity as well as control tissue inflammation. TLRs are implicated in adrenal cell turnover and steroidogenesis during inflammation. Therefore, TLRs play a crucial role in the activation of adrenal inflammation mediating adrenal gland dysfunction during septicemia. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

[...]L'ensemble de nos études soulignent le rôle important du stress oxydant qui est lié à la stimulation du SRAA dans la survenue de la dysfonction endothéliale chez le rat présentant une cirrhose biliaire. L'action sur des facteurs pouvant induire le stress oxydant comme la translocation bactérienne et le traitement par des antioxydants (polyphénols) ont clairement montré leurs actions bénéfiques chez nos rats cirrhotiques. Le rôle du NO, en tous cas en tant que vasodilatateur pur, n'est peut-être pas primordial ce qui peut expliquer les résultats décevants en clinique publiés parcertains auteurs. / [...]The important role of oxidative stress in the development of endothelial dysfonction in rats with biliary cirrhosis is emphasized in our studies. Oxidative stress is associated with the stimulation of the RAAS and bacterial translocation. Treatment with antioxidants (polyphenols) and probiotics have clearly demonstrated their beneficial effects on the endothelial dysfonction in our cirrhotic rats. The role of NO as a pure vasodilator is perhaps not essential which may explain the disappointing clinical results published by some authors.

Chronic pancreatitis (CP) is a heterogeneous disease defined as chronic inflammatory changes of the pancreatic tissue caused by variety of aetiologies. Oxidative stress accompanying the inflammatory processes has been suggested as an important factor contributing to CP development. The aim of this study was to determine levels of lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), together with nitrites, the total antioxidant capacity, cytokines, biochemical and haematological parameters in the plasma of patients with CP and control subjects. Levels of MDA and 4-HNE were analyzed using high-performance liquid chromatography. The total antioxidant capacity of plasma against peroxyl radicals was evaluated using chemiluminescence determination. Nitrites were determined using Griess reaction. Cytokines - TNF-alfa; TNF RI; PDGF-AB; TGF-beta, together with myeloperoxidase and hyaluronan were determined using ELISA Kits. Biochemical and haematological parameters were measured by standard methods.

Adrenal gland insufficiency – the clinical manifestation of deficient production or action of adrenal steroids – is a life-threatening disorder. Among many factors which can predispose to primary adrenal failure, an autoimmune adrenalitis and infectious agents play a major role. The initial host defense against bacterial infections is executed primarily by the pattern recognition receptors, e.g. Toll-like receptors (TLRs), expressed in cells from the innate immune system. Upon activation, TLRs have been found to regulate various levels of innate and adaptive immunity as well as control tissue inflammation. TLRs are implicated in adrenal cell turnover and steroidogenesis during inflammation. Therefore, TLRs play a crucial role in the activation of adrenal inflammation mediating adrenal gland dysfunction during septicemia. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Over the past few years the NAD-related compounds nicotinamide (NAM), nicotinamide riboside (NR) and 1-methylnicotinamide (MNA) have been established as important molecules in signalling pathways that contribute to metabolic functions of many cells, including those of the immune system. Among immune cells, monocytes/macrophages, which are the major players of inflammatory processes, are especially susceptible to the anti-inflammatory action of NAM. Here we asked whether NAM and the two other compounds have the potential to regulate differentiation and LPS-induced biological answers of the monocytic cell line THP-1. We show that treatment of THP-1 cells with NAM, NR and MNA resulted in growth retardation accompanied by enrichment of cells in the G0/G1-phase independent of p21 and p53. NAM and NR caused an increase in intracellular NAD concentrations and SIRT1 and PARP1 mRNA expression was found to be enhanced. The compounds failed to up-regulate the expression of the cell surface differentiation markers CD38, CD11b and CD14. They modulated the reactive oxygen species production and primed the cells to respond less effectively to the LPS induced TNF-a production. Our data show that the NAD metabolites interfere with early events associated with differentiation of THP-1 cells along the monocytic path and that they affect LPS-induced biological responses of the cell line.

No description available.

Upon encounter of an antigen, epidermis-resident Langerhans cells (LCs) become activated and present the processed antigen to T cells of the draining lymph nodes, resulting in tolerogenic or inflammatory responses. In psoriasis plaques, skin homeostasis is disrupted and replaced by an inflammatory dermatitis. Topical application of the anti-viral compound, imiquimod, induces a psoriasiform inflammatory condition, partly driven by LC production of pro-inflammatory cytokines. Differentiation of the myeloid progenitor cell line, MUTZ-3, produces MUTZ-3 derived Langerhans cells (MUTZ-LCs) which can be used as an in vitro model of LCs. This project aimed to investigate the phenotype and function of imiquimod-treated MUTZ-LCs in monolayer cultures, co-culture with T cells and inserted into a 3D skin model. LC-related surface markers (HLA-DR, CD1a, CD207, CCR7) were upregulated in MUTZ-LCs after 7 days of differentiation with 40 ng/ml GM-CSF, 10 ng/ml TGF-β and 2.5 ng/ml TNF-α. Supernatants of imiquimod-treated monolayer cultures of MUTZ-LCs showed subtle concentrations of IL-6 and TNF-α, but not IL-23. mRNA expression showed no significant upregulation of IL-6, IL-23 or TNF-α after 24 h treatment with imiquimod. The presence of MUTZ-LCs in T cell co-cultures greatly increased the production of IL-2, but did not affect expression of CD25. After 16 h exposure to imiquimod, IL-6, IL-23 and TNF-α could not be detected in culture supernatants of a 3D model consisting of fibroblasts, keratinocytes and MUTZ-LCs. The model was devoid of fibroblasts after 19 days of culture, most likely compromising the immunocompetence, as LC migration in response to activation could not be detected. Further studies could refine and optimize the imiquimod-3D skin model, which has potential as a possible substitute for animal models in psoriasis research.

Over the past few years the NAD-related compounds nicotinamide (NAM), nicotinamide riboside (NR) and 1-methylnicotinamide (MNA) have been established as important molecules in signalling pathways that contribute to metabolic functions of many cells, including those of the immune system. Among immune cells, monocytes/macrophages, which are the major players of inflammatory processes, are especially susceptible to the anti-inflammatory action of NAM. Here we asked whether NAM and the two other compounds have the potential to regulate differentiation and LPS-induced biological answers of the monocytic cell line THP-1. We show that treatment of THP-1 cells with NAM, NR and MNA resulted in growth retardation accompanied by enrichment of cells in the G0/G1-phase independent of p21 and p53. NAM and NR caused an increase in intracellular NAD concentrations and SIRT1 and PARP1 mRNA expression was found to be enhanced. The compounds failed to up-regulate the expression of the cell surface differentiation markers CD38, CD11b and CD14. They modulated the reactive oxygen species production and primed the cells to respond less effectively to the LPS induced TNF-α production. Our data show that the NAD metabolites interfere with early events associated with differentiation of THP-1 cells along the monocytic path and that they affect LPS-induced biological responses of the cell line.

Fatigue is a prevalent and debilitating symptom that affects up to 97% of individuals with multiple sclerosis (MS). It can negatively influence the socioeconomic status, activities of daily living and quality of life for the affected individuals. Fatigue is multidimensional and abstract, thereby making it complex to understand, target and treat. Over the past 20 years, physical activity has become more recognized as a management method that could help with the alleviation of fatigue. One of the reasons could be due to the anti-inflammatory effects of exercise. However, due to the multi-factorial nature of fatigue and the heterogeneity of the training intervention protocols, the potential mechanisms that underlie the relationship between fatigue and exercise are still not fully understood. In 2013, Latimer-Cheung and colleagues developed an evidence based physical activity guideline (PAGs) for people with MS. Since then, studies have shown consistent beneficial effects of exercise on reducing fatigue in people with MS by adhering to the PAGs. To date, however, there are no published studies that examined the potential mechanism that underlie the beneficial effect of the PAGs on reducing fatigue. The primary purpose of this thesis was to evaluate the effects of adhering to the PAGs on fatigue in people with MS and to assess whether any exercise-induced changes in fatigue were associated with changes in inflammatory cytokines. The secondary purpose of this thesis was to evaluate the effects of exercise on depression, strength, aerobic fitness, muscular endurance and quality of life. This study had a wait-list control design. Participants with relapse remitting multiple sclerosis (RRMS) were recruited and randomized to begin with either a 12-week supervised exercise training program (G1) or a wait-list control period (G2). The training program involved at least 30 minutes aerobic training and resistance training for major muscle groups twice per week. The G2 group maintained their regular lifestyle. After 12 weeks, G1 reverted back to their usual lifestyle and G2 began their 12-week supervised exercise training. Following training, we found a reduction in fatigue and depression with increased strength and quality of life. No changes were observed in pro-inflammatory cytokines, aerobic fitness or muscular endurance. This is the first study that examined the underlying potential mechanism for the beneficial effects of exercise by adhering to the PAGs. Following the PAGs for 12 weeks results in significant improvements in fatigue, depression, strength and quality of life. However, our results do not support the role of inflammatory cytokines in mediating these improvements. / Thesis / Master of Science in Kinesiology

Necrotizing enterocolitis (NEC) is a multifactorial intestinal disease involving systemic inflammatory responses in preterm infants. It affects 1–10% of all newborns (NB) admitted to the neonatal intensive care unit and has an overall mortality rate ranging between 10% in mild disease to 100% in more severe cases, yet survivors still suffer life-long complications. The pathogenesis of necrotizing enterocolitis (NEC) involves multiple factors that lead to inflammation of the intestines and subsequent injury to the intestinal epithelial barrier. Maintenance of barrier integrity is due in part to tight junction proteins, such as zona occludens-1 (ZO-1) and occludin. Previous work has shown that cytokines belonging to the IL-12 family, namely IL-12 and IL-23, alter ZO-1 and cause barrier dysfunction in cellular and animal models. It is still unclear whether initial breakdown is mediated through IL-12 Receptor (R) or IL-23 Receptor (R). Newly described cytokines belonging to this family may also play a role in the recovery mechanism. In our study, we propose that recovery occurs when the EBI3 subunit from the anti-inflammatory cytokine, IL-27, binds to the gp130 receptor on intestinal epithelial cells, activating STAT3, later inhibiting NF-κB activation, and thus, reducing pro-inflammatory cytokine production and subsequent ZO-1 breakdown. Elucidating the inflammatory pathway and major cytokines involved contributes to the largely unknown etiology and pathogenesis of the disease, as well as serve as a basis for the development of a screening protocol.