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Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-γ promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated 'danger signal' such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy. [ABSTRACT FROM AUTHOR]

The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and rate-limiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-β and interferon-γ and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal–fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-γ-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood–brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan. [ABSTRACT FROM AUTHOR]

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. Key messages: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible. [ABSTRACT FROM AUTHOR]

Lymph node metastases occur frequently during the progression of many types of cancer, and their presence often reflects poor prognosis. The drainage of tumor-derived factors such as antigens, growth factors, cytokines, and exosomes through the lymphatic system to the regional lymph nodes plays an important role in the pre-metastatic conditioning of the microenvironment in lymph nodes, making them receptive and supportive metastatic niches for disseminating tumor cells. Modified immunological responses and remodeling of the vasculature are the most studied tumor-induced pre-metastatic changes in the lymph node microenvironment that promote metastasis, although other metastasis-relevant alterations are also starting to be studied. Here, I review our current understanding of the lymph node pre-metastatic niche, how tumors condition this niche, and the relevance of this conditioning for our understanding of the process of metastasis. [ABSTRACT FROM AUTHOR]

Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as tumor necrosis factor (TNF)-α in rheumatoid arthritis (RA) and interferon (IFN)-α/γ in systemic lupus erythematosus (SLE). To relate the transcriptional imprinting of cytokines in a cell type- and disease-specific manner, we generated gene expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro -generated signatures induced by TNF-α, IFN-α2a, and IFN-γ. Monocytes from SLE and RA patients revealed disease-specific gene expression profiles. In vitro-generated signatures induced by IFN-α2a and IFN-γ showed similar profiles that only partially overlapped with those induced by TNF-α. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNF-α regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNF-α that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene expression profiles, which can be molecularly dissected when compared with in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

IRX-2, a natural cytokine biological with multiple components, has been used in preclinical and clinical studies to promote antitumor activity of T lymphocytes. To define cellular mechanisms responsible for antitumor effects of IRX-2, its ability to induce effector T cells (Teff) was examined in a model simulating the tumor microenvironment. An in vitro model containing conventional CD4CD25 cells co-cultured with autologous immature dendritic cells, irradiated tumor cells, and cytokines was used to study differentiation and expansion of regulatory T cells (Treg) and Teff in the presence and absence of IRX-2. Phenotype, suppressor function, signaling, and cytokine production were serially measured using flow cytometry, Western blots, CFSE-based suppressor assays, and Luminex-based analyses. The presence of IRX-2 in the co-cultures promoted the induction and expansion of IFN-γTbet Teff and significantly ( p < 0.01) decreased the induction of inducible IL-10TGF-β Treg. The responsible mechanism involved IFN-γ-driven T cell polarization towards Teff and suppression of Treg differentiation. In an in vitro model simulating the human tumor microenvironment, IRX-2 promoted Teff expansion and antitumor activity without inducing Treg. Thus, IRX-2 could be considered as a promising component of future antitumor therapies. [ABSTRACT FROM AUTHOR]

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed. [ABSTRACT FROM AUTHOR]

Recognition of pathogenic microbes by the innate immune system is based on the principle of pathogen-associated molecular patterns (PAMPs). These are conserved molecular structures that are present in the pathogen but not in the host. Cells of the innate immune system or, in some cases, virtually all cells of our body express receptors that are able to specifically recognize PAMPs and trigger the appropriate responses including the production of cytokines. In the case of viruses, an interesting complication exists: Viruses use the host's cellular metabolism and building blocks to replicate. As a consequence, protein modifications, lipid or carbohydrate configurations restricted to viruses do not exist. Instead, parts of the innate immune system have evolved to detect viral nucleic acids mainly by virtue of their (non-physiological) localization and structure. Understanding the molecules involved in anti-viral defence and the patterns they recognize will allow harnessing them for therapeutic strategies targeting viral and autoimmune diseases and tumours. This review presents important recent advances in understanding intracellular recognition of nucleic acid patterns by the innate immune system. [ABSTRACT FROM AUTHOR]

Neutrophil granulocytes are important mediators of innate immunity, but also participate in the pathogenesis of (auto)inflammatory diseases. Neutrophils express a specific set of proteolytic enzymes, the neutrophil serine proteases (NSPs), which are stored in cytoplasmic granules and can be secreted into the extra- and pericellular space upon cellular activation. These NSPs, namely cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3), have early been implicated in bacterial defense. However, NSPs also regulate the inflammatory response by specifically altering the function of cytokines and chemokines. For instance, PR3 and NE both inactivate the anti-inflammatory mediator progranulin, which may play a role in chronic inflammation. Here, we provide a concise update on NSPs as modulators of inflammation and discuss the biological and pathological significance of this novel function of NSPs. Mounting evidence support an important proinflammatory function for PR3, which may have been underestimated in the past. [ABSTRACT FROM AUTHOR]

IL-22 is an IL-10 family cytokine member that was recently discovered to be produced by Th17 cells. Current studies have revealed that IL-22 targets cells of the digestive, skin, and respiratory organ systems and plays an important role in mucosal immunity. The IL-22 receptor (IL-22R) is expressed exclusively in these tissues, thereby allowing the cytokine to mediate epithelial innate immunity in response to a variety of pathogens. Although recent studies have shown the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung), there is evidence that IL-22 also plays a role in autoimmune disease, such as psoriasis. IL-22 therefore, not unlike other cytokines, has complex pro-inflammatory, anti-inflammatory, and autoimmune effects which continue to be under further investigation. This review will focus on what is known about IL-22 and its function in mucosal host defense. [ABSTRACT FROM AUTHOR]

Classical experimental models of hemorrhage are characterized by the use of anesthetics that may interfere with the typical immune responses and pathology of hemorrhage/resuscitation. Thus, therapeutic strategies successful in anesthetized animals might not be beneficial in clinical trials. In this study, we analyzed whether ethyl pyruvate could provide therapeutic benefits during resuscitation in awake (unanesthetized) hemorrhage. Our results indicate that hemorrhage in unanesthetized animals required approximately 25% higher blood withdrawal than anesthetized animals to achieve the same targeted mean arterial blood pressure. Resuscitation with Hextend reestablished circulatory volume and improved survival during resuscitation of awake rodents. Yet, over 75% of the animals resuscitated with Hextend died within the first hours after hemorrhage. Resuscitation with Hextend containing 50 mM ethyl pyruvate protected over 87% of the animals. This survival benefit did not correlate with significant changes in the metabolic markers but with an anti-inflammatory potential during resuscitation. Unlike classical hemorrhage in anesthetized animals, ethyl pyruvate reestablished mean arterial blood pressure significantly earlier than Hextend in unanesthetized rodents. Unanesthetized animals showed twofold higher serum tumor necrosis factor (TNF)-α than anesthetized animals subjected to the same blood pressure. This process was not due to the response of a single organ, but affected all the analyzed organs including the lung, heart, spleen, and liver. Although resuscitation with Hextend failed to attenuate systemic TNF-α levels, it inhibited TNF-α levels in the lung, heart, and liver but not in the spleen. Unlike Hextend, resuscitation with ethyl pyruvate prevented high serum TNF-α levels and blunted TNF-α responses in all the organs including the spleen. These studies indicate that the inflammatory responses in anesthetized animals differ from that in unanesthetized animals and that awake hemorrhage can provide advantages in the study of anti-inflammatory strategies during resuscitation. Ethyl pyruvate may attenuate systemic inflammatory responses during resuscitation and improve survival in experimental models of awake hemorrhage. [ABSTRACT FROM AUTHOR]

Hepcidin, a small cationic liver derived peptide, is a master regulator of body iron homeostasis. Cytokines and iron availability have so far been identified as regulators of hepcidin expression. Herein, we investigated the functional role of Kupffer cells for hepcidin expression because of their vicinity to the hepatocytes and their importance for iron recycling via erythrophagocytosis. We investigated C57Bl6 mice and littermates, in which Kupffer cells were eliminated in vivo upon intravenous injection of liposome-encapsulated clodronate. Primary cultures of hepatocytes and Kupffer cells were used to study direct regulatory effects ex vivo. The in vivo depletion of Kupffer cells resulted in a significant increase in liver hepcidin expression, which was paralleled by a significant reduction in serum iron levels. The same pattern of regulation by Kupffer cell depletion was observed upon injection of bacterial lipopolysaccharide into mice and in primary (Hfe −/−) and in secondary iron-overloaded mice. Accordingly, the messenger ribonucleic acid (mRNA) concentrations of the hepcidin iron-sensing molecule hemojuvelin were not significantly changed upon Kupffer cell depletion. When primary hepatocytes were cocultivated with Kupffer cells or stimulated with a Kupffer cell-conditioned medium ex vivo, a significant reduction in hepatocyte hepcidin mRNA expression was observed. Our data suggest that Kupffer cells control body iron homeostasis by exerting negative regulatory signals toward hepcidin expression, which may be primarily referred to the secretion of yet unidentified hepcidin-suppressing molecules by Kupffer cells. [ABSTRACT FROM AUTHOR]

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-α has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNFRSF1B) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSF1B is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSF1B in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSF1B marker with CAD (χ2=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs. absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1–9.4, P<0.0001; in CA16 heterozygotes or was 1.3, 95% CI 0.94–1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs. 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20–0.52, P<0.0001; in heterozygotes OR 0.41, 95% CI 0.26–0.63, P<0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0–1.9, P=0.027). Apolipoprotein A-I was elevated (P<0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1±0.1 ng/ml in CAD vs. 3.2±0.1 in control (P<0.0001), 5.2±0.1 in the presence vs. 4.6±0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2±0.2 (no angina), 5.0±0.1 (stable angina), 5.4±0.2 (unstable angina; P=0.003). sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor β and homocysteine and was influenced by TNFRSF1B genotype. Thus genetic variation in or near the TNFRSF1B locus may predispose to CAD. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinases are cell-bound, membrane-spanning receptors that transduce growth factor dependent signals to the intracellular environment. Their catalytic cytoplasmic domains share a high level of sequence similarity, but their extracellular portions usually have a highly variable, multiple-domain structure. In a growing number of cases immunoglobulin-like domains contained within the extracellular portion have been shown to contain the ligand-binding site. In recent years experimental three-dimensional structures have been determined for some of these domains, free or in complex with their ligand. Here we review current structural information on these immunoglobulin-like domains and the growth factors that bind to them, with an emphasis on the vascular endothelial growth factor, nerve growth factor, and fibroblast growth factor systems. [ABSTRACT FROM AUTHOR]

While many advances have been made in the treatment of patients with cancer, significant challenges that remain include tumor cell resistance and the toxicity associated with currently used intensive chemotherapeutic regimens. This is particularly true for patients with acute myelogenous leukemia (AML). Most patients with AML usually are able to achieve complete remission, but only a minority obtain long-term survival. In addition, much of the success achieved has been due to escalation of chemotherapeutic dosing and hematopoietic stem cell transplantation. There is thus a great need for improved therapies which would ideally be able to circumvent drug resistance and more specifically target leukemic cells. Advances in immunobiology over the past century have led to new hope for the development of immune-mediated vaccine therapies for patients with cancer. This review focuses on the development of vaccine approaches for treatment of AML and some of the potential advantages and problems. [ABSTRACT FROM AUTHOR]

One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune diseases. [ABSTRACT FROM AUTHOR]