The pathogenesis of inflammatory liver diseases and development of liver fibrosis involves hepatocytes as well as non-parenchymal liver cells like resident liver macrophages (Kupffer cells (KC)), Stellate cells and endothelial cells. Kupffer cells play a critical role in liver (patho)physiology and in the defense of the liver during inflammation. They constitute about 50% of non-parenchymal cells and are the largest population of tissues macrophages in the body. Infections, toxins (lipopolysacharide (LPS)), parenchymal damage and stresses stimulate the inflammatory response of Kupffer cells with the following secretion of bioactive factors, cytotoxicity, antigen processing, etc. Resident liver macrophages are the main producers of inflammatory mediators in the liver. Among them there are prostanoids (prostaglandin (PG) E2 and thromboxane (Tx) A2), cytokines (e.g. interleukin (IL)-1,-6, -10, tumor necrosis factor (TNF) α) and inorganic mediators like nitric oxide (NO). Macrophages-derived products play opposing roles in the development of liver fibrogenesis: IL-1β, TNFα, IL-6, transforming growth factor (TGF)-β and TxA2 (pro-fibrogenic mediators) promote whereas PGE2, IL-10 and nitric oxide (anti-fibrogenic mediators) suppress liver fibrogenesis. The present study shows the production of PGE2 and TxA2 by resident liver macrophages upon prolonged activation by LPS and the characterization of biosynthesis pathways. The production of PGE2 and TxA2 is followed during 24 h after stimulation of macrophages with LPS. The involvement of enzymes is measured on the RNA level (RT-PCR), protein level (Western blot analysis) and activity (activity assays), respectively. The amounts of released prostanoids are measured at time points 2, 4, 8 and 24 h after LPS stimulation. The production of PGE2 is very low without stimulation, shows a delay within the first few hours after stimulation with LPS, and thereafter linearly increases up to 24 h. TxA2 production is very low without stimulation, and increases without a time-delay after the addition of LPS. Prostanoid biosynthesis is inhibited by dexamethasone. The present study shows the involvement and regulation of the AA cascade by the following enzymes: cPLA2: is expressed in resting Kupffer cells; cPLA2 expression and phosphorylation is increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. COX-1: is expressed in resting Kupffer cells; COX-1 expression is not influenced by LPS and dexamethasone. The COX-1 inhibitor SC560 suppresses the LPS-induced production of PGE2 and TxA2 (8h and 24h), localization predominantly in membrane fraction. COX-2: is almost not expressed in resting Kupffer cells; COX-2 expression is highly increased by LPS, dexamethasone suppresses the LPS effect. The COX-2 inhibitor SC236 inhibits the production of PGE2 and TxA2 at 8h by about 77% and 20%, and at 24h by about 42% and 34%, respectively, localization predominantly in membrane fraction. mPGES-1: is almost not expressed in resting cells; mPGES-1 expression is highly increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. mPGES-2: is expressed in resting Kupffer cells; mPGES-2 expression is slightly increased by LPS, localization predominantly in membrane fraction. cPGES: is expressed in resting Kupffer cells; LPS has no effect, localization predominantly in soluble fraction. TxA2 synthase: is expressed in resting Kupffer cells; LPS and dexamethasone have no effect, localization predominantly in membrane fraction. Treatment of Kupffer cells with IL-1ß and TNF-α leads to an enhanced release of PGE2 and TxA2 and upregulate the expression of cPLA2, COX-2 and mPGES-1. IL-6 has no effect on prostanoid production. In contrast, IL-10 suppresses the LPS-induced production of PGE2 and TxA2 and expression of cPLA2, COX-2 and mPGES-1. Resting Kupffer cells release very low amounts of NO and do not express iNOS, nNOS and eNOS. LPS, TNF-α and IL-1ß upregulate NO release and the expression of iNOS whereas dexamethasone and IL-10 downregulate NO release and the expression of iNOS. PGE2 suppresses the LPS-induced release of NO but enhances the cytokine-induced release of NO. NO induces a release of PGE2. Thus, the study demonstrates a crosstalk between prostanoids, nitric oxide and cytokines in Kupffer cells under inflammatory conditions and demonstrates a possible anti-fibrogenic effect of PGE2 in the process of liver fibrogenesis.

Purpose Allergy against implant materials is discussed controversially and still not fully understood. Despite these controversies, a relevant number of patients receive hypoallergenic knee implants. The aim of this study was to compare a new coating system with the standard implant in total knee arthroplasty (TKA). Additionally, the influence of proinflammatory cytokines on patient-reported outcome measures (PROMs) was investigated. Methods 120 patients without known metal allergy and without previous metal implants were included. The patients were randomized to receive a coated or standard TKA of the same knee system. 105 patients completed the 5 year follow-up. Patient-reported outcome measures (PROMs) including knee function (Oxford Knee Score, OKS), quality of life (SF36) and UCLA activity scale were assessed. Additionally, several cytokines with a possible role in implant allergy were measured in patient`s serum (IL-1beta, IL-5, IL-6, IL-8, IL-10, IP-10, IFN γ, TNF α). Group comparison was performed using Mann–Whitney U test for continuous values and chi-square test for categorical values. Results There were no differences in PROMs between both groups at any follow-up. The majority of patients demonstrated no elevation of the measured blood cytokines. The blood cytokine pattern after 5 years demonstrated no differences between study groups. There was a significant association between elevated IL-8 values and worse results in the overall OKS (p = 0.041), the OKS function component (p = 0.004), the UCLA activity scale (p = 0.007) and the physical component of SF36 (p = 0.001). Conclusion There were no problems with the new coating during mid-term follow-up and no differences in PROMs between coated and standard TKA. Patients with an increased inflammatory response demonstrated worse functional results, regardless of the implant. Level of evidence I. Clinical trial registration The study protocol was registered in the US National Institutes of Health’s database (http:// www.clini caltr ials. gov) registry under NCT00862511.

Die bakterielle Meningitis (BM) ist trotz antibiotischer Therapie eine Erkrankung mit einer hohen Mortalität und Morbidität. Kopfschmerzen und Meningismus sind Hauptsymtome und ein klinischer Hinweis für die Aktivierung trigeminaler Fasern. Ziel dieser Arbeit war es zu prüfen ob die freigesetzten Neuropeptide einen proinflammatorischen Effekt auf zerebrale Endothelzellen, einen wesentlichem Bestandteil der Blut-Hirn-Schranke haben. Wir verwendeten primär kultivierte zerebrale Kapillarendothelzellen (BMEC) der Ratte und als Stimulus Neuropeptide und/oder Pneumokokkenzellwände (PCW). Beide Neuropeptide, CGRP mehr als SP, verstärken den Effekt von PCW auf die mRNA Expression und Freisetzung von TNF-alpha, IL-1beta, IL-6, IL-10 und MIP-2 aus den BMEC. CGRP und SP haben nur eine geringe Wirkung. PCW regulieren die Dichte der CRLR (CGRP1-R) bzw. NK-1 Rezeptoren und erklären damit die kostimulatorische Wirkung. Zudem untersuchten wir den Effekt von PCW und/oder CGRP auf die Adrenomedullin (AM)- Synthese. AM ist ein vasodilatorisch wirkendes Peptid, dass vorwiegend in Endothelzellen konstitutiv gebildet wird und am CRLR Rezeptor wirkt. PCW und CGRP verstärken die Synthese von AM. Mit dieser Arbeit konnte gezeigt werden, dass PCW zur Hochregulation von Neuropeptidrezeptoren führt und CGRP und SP über diese Rezeptoren einen modulatorischen Effekt auf die Zytokinproduktion in BMEC haben. Ein genaues Verständnis dieser Interaktionen könnte die Entwicklung immunmodulatorischer Interventionen und damit eine Verbesserung der Prognose der bakteriellen Meningitis bewirken. / Despite antibiotic treatment bacterial meningitis is still associated with a high mortality and morbidity. Headache and meningismus as key symptoms, provide clear evidence for the activation of trigeminal nerve fibers. Aim of the study was to test whether the released neuropeptides have a proinflammatory effect in cerebral endothelial cells the major compartment of the blood brain barrier. We used primary brain microvascular endothelial cells of the rat (BMEC) which were stimulated with CGRP, SP and/or pneumococcal cell walls (PCW). Both neuropeptides CGRP more than SP enhanced PCW-induced mRNA expression and the release of TNF-alpha, IL-1-beta, IL-6, IL-10 and MIP-2. Neuropeptides alone were not able to induce these cytokines. PCW upregulate the density of CRLR receptor and regulate the NK-1 receptor and therefore may explain the costimulatory effect. Furthermore the effect of PCW and/or CGRP on adrenomedullin synthesis in BMEC was investigated. Adrenomedullin is a vasodilatatory peptide, which is constitutivly produced by endothelial cells and act on the CRLR receptor. PCW as well as CGRP enhance the synthesis of AM. Our data suggest that PCW upregulate neuropeptide receptors and modulate via these specific receptors the cytokine production. A detailed understanding of these interactions may open new immunmodulatory interventions and therefore may contribute to a better prognosis of bacterial meningitis.

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The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.