Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain-immune interface.

Systemic inflammation shifts the brain microenvironment towards a proinflammatory state. However, how peripheral inflammation mediates changes in the brain remains to be clarified. We aimed to identify hippocampal cells and cytokines that respond to endotoxemia. Mice were intraperitoneally injected with lipopolysaccharide (LPS) or saline, and examined 1, 4, and 24 h after injection. Tissue cytokine concentrations in the spleens and hippocampi were determined by multiplex assays. Another group of mice were studied immunohistologically. Fourteen cytokines showed an increased concentration in the spleen, and 10 showed an increase in the hippocampus after LPS injection. Cytokines increased at 4 h (CCL2, CXCL1, CXCL2, and interleukin-6) were expressed by leptomeningeal stromal cells, choroid plexus stromal cells, choroid plexus epithelial cells, and hippocampal vascular endothelial cells, all of which were located at the brain-immune interface. Receptors for these cytokines were expressed by astrocytic endfeet. Cytokines increased at 24 h (CCL11, CXCL10, and granulocyte-colony stimulating factor) were expressed by astrocytes. Cells of the brain-immune interface therefore respond to endotoxemia with cytokine signals earlier than hippocampal parenchymal cells. In the parenchyma, astrocytes play a key role in responding to signals by using endfeet located in close apposition to the interface cells via cytokine receptors.

La soja en la prevención de la enfermedad cardiovascular / Soy in the prevention of cardiovascular disease

Los alimentos de soja o aislados de proteína de soja contienen dos componentes bioactivos principales, las isoflavonas (ISF) asociadas con la proteína de soja y los péptidos generados a partir de las dos principales proteínas de la soja, B-conglicina y la glicina. Algunos componentes de la dieta con soja controlan las funciones de adhesión del endotelio vascular, mediante la regulación de los mecanismos claves de control de las moléculas de adhesión endoteliales, la función de la integrina en los monocitos, citoquinas y quimoquinas en el control del tráfico y migración de los monocitos. También podrían regular la oxLDL en la generación y regulación de la expresión de los recogedores de radicales libres. La dieta con soja y otras dietas con efectos antiinflamatorios pueden bloquear el proceso inflamatorio asociado con la aterogénesis, reduciendo así el riesgo de ECV. Se requieren de más estudios que aclaren tanto a nivel experimental como clínico los mecanismos de acción de las ISF en la protección cardiovascular (AU)

Soy food or soybean protein isolates contain two major bioactive components, isoflavones (ISF) associated with soy protein, and peptides generated from two major soybean protein, B-conglycinin and glycine. Some components of the diet with soybean control the functions of vascular endotelial adhesion, by regulating the control key mechanisms of endothelial adhesion molecules, integrin function in monocytes, cytokines and chemokines in the traffic control and migration of monocytes. OxLDL may also regulate the generation and regulation of expression of catchers of free radicals. The diet with soy and other anti-inflammatory diets can block the inflammatory process associated with atherogenesis, thus reducing the risk of CVD. Further studies are required to clarify both experimental and clinical mechanism of action of the ISF cardiovascular protection (AU)

[Cytokines in bone diseases. What is cytokine?].

Cytokines have an essential role for cell-cell communication. They can regulate cell proliferation, differentiation, survival, and function. Interaction of cell surface receptor with cytokines is necessary for control of physiological responses. Activation of cytokine receptors transduces specific signal in the receptor-expressing cells, resulting that cytokines can regulate specific cell population. Thus, cytokines contribute directly or indirectly to morphogenesis, host defense and immune response, play critical roles for homeostasis and development.

Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3.

Interferon (IFN)-lambdas, including INF-lambda1, -lambda2, and -lambda3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. IFN-lambda1, -lambda2, and -lambda3 bind to the same receptor (known as IL28RA) to exert their antiviral, antitumor and immunomodulatory effects. Here, we identified IL28RA genes from the genome of human, chimpanzee, macaque, orangutan, mouse, horse, rat, dog, chicken, and found that only one IL28RA existed in each genome. All the identified IL28RAs are single-pass type I membrane proteins except chicken IL28RA. They belong to the type II cytokine receptor family and contain one fibronectin type-III domain. We found human IL28RA was expressed in lymphs, testes, lymphoma, teratocarcinoma, pediatric pre-B cell acute lymphoblastic leukemia, germinal center B cells, embryonic stem cells, fetal lung, and also expressed in bladder, blood and breast cancers, glioma, head and neck cancer and lung cancer tissues. Three tumor-related transcriptional factor binding sites (AP-2, c-Jun and P53) were identified within the 1.0-kb regions upstream of the transcriptional start site of human IL28RA. Meta-analysis of the prognostic value of IL28RA genes in various cancers found that the expression of IL28RA was indeed related to the cancer prognosis in certain cancers. The STAT1 binding sites in the promoter region of IL28RA implied a specific mechanism for the amplifying effects of IFN-lambdas. The LyF-1 binding sites in the promoter region of IL28RA imply that IFN-lambdas were involved in the differentiation of early B and T cells.

EPOC y cáncer de pulmón / Chronic Obstructive Pulmonary disease and lung cancer

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Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor.

From a patient with acute myeloid leukemia (AML), we have identified IL-27Ra (also known as TCCR and WSX1) as a gene whose expression can induce the transformation of hematopoietic cells. IL-27Ra (IL-27R) is a type I cytokine receptor that functions as the ligand binding component of the receptor for IL-27 and functions with the glycoprotein 130 (gp130) coreceptor to induce signal transduction in response to IL-27. We show that IL-27R is expressed on the cell surface of the leukemic cells of AML patients. 32D myeloid cells transformed by IL-27R contain elevated levels of activated forms of various signaling proteins, including JAK1, JAK2, STAT1, STAT3, STAT5, and ERK1/2. Inhibition of JAK family proteins induces cell cycle arrest and apoptosis in these cells, suggesting the transforming properties of IL-27R depend on the activity of JAK family members. IL-27R also transforms BaF3 cells to cytokine independence. Because BaF3 cells lack expression of gp130, this finding suggests that IL-27R-mediated transformation of hematopoietic cells is gp130-independent. Finally, we show that IL-27R can functionally replace a homodimeric type I cytokine receptor in the activation of JAK2-V617F, a critical JAK2 mutation in various myeloproliferative disorders (MPDs). Our data demonstrate that IL-27R possesses hematopoietic cell-transforming properties and suggest that, analogous to homodimeric type I cytokine receptors, single-chain components of heterodimeric receptors can also enhance the activation of JAK2-V617F. Therefore, such receptors may play unappreciated roles in MPDs.

Cytokine receptors and hematopoietic differentiation.

Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.

Evolution of Class I cytokine receptors.

BACKGROUND: The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio). RESULTS: Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals. CONCLUSION: This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred.

Protein hormones and immunity.

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.

Interleukins and STAT signaling.

Metazoan cells secrete small proteins termed cytokines that execute a variety of biological functions essential for the survival of organisms. Binding of cytokines that belong to the hematopoietin- or interferon-family, to their cognate receptors on the surface of target cells, induces receptor aggregation, which in turn sequentially triggers tyrosine-phosphorylation-dependent activation of receptor-associated Janus-family tyrosine kinases (JAKs), receptors, and signal transducers and activators of transcription (STATs). Phosphorylated STATs form dimers that migrate to the nucleus, bind to cognate enhancer elements and activate transcription of target genes. Each cytokine activates a specific set of genes to execute its biological functions with a certain degree of redundancy. Cytokine signals are, in general, transient in nature. Therefore, under normal physiological conditions, initiation and attenuation of cytokine signals are tightly controlled via multiple cellular and molecular mechanisms. Aberrant activation of cytokine signaling pathways is, however, found under a variety of patho-physiological conditions including cancer and immune diseases.

High dynamic range characterization of the trauma patient plasma proteome.

Although human plasma represents an attractive sample for disease biomarker discovery, the extreme complexity and large dynamic range in protein concentrations present significant challenges for characterization, candidate biomarker discovery, and validation. Herein we describe a strategy that combines immunoaffinity subtraction and subsequent chemical fractionation based on cysteinyl peptide and N-glycopeptide captures with two-dimensional LC-MS/MS to increase the dynamic range of analysis for plasma. Application of this "divide-and-conquer" strategy to trauma patient plasma significantly improved the overall dynamic range of detection and resulted in confident identification of 22,267 unique peptides from four different peptide populations (cysteinyl peptides, non-cysteinyl peptides, N-glycopeptides, and non-glycopeptides) that covered 3,654 different proteins with 1,494 proteins identified by multiple peptides. Numerous low abundance proteins were identified, exemplified by 78 "classic" cytokines and cytokine receptors and by 136 human cell differentiation molecules. Additionally a total of 2,910 different N-glycopeptides that correspond to 662 N-glycoproteins and 1,553 N-glycosylation sites were identified. A panel of the proteins identified in this study is known to be involved in inflammation and immune responses. This study established an extensive reference protein database for trauma patients that provides a foundation for future high throughput quantitative plasma proteomic studies designed to elucidate the mechanisms that underlie systemic inflammatory responses.

Full house: 12 receptors for 27 cytokines.

With the sequencing of the human genome nearing completion, it appears that all members of the class II cytokine receptor family (CRF2) have been identified and partially characterized. The entire family is composed of exactly one dozen members. Eleven of them combine as various heterodimers to transduce signals across the cellular membrane for 27 cytokines divided into four structurally related groups: 6 cytokines of the IL-10 family, 17 type I IFNs, 1 type II IFN and 3 IFN-lambdas. The last CRF2 member is the soluble receptor which can neutralize the action of one of the cytokines of the IL-10 family, IL-22. Although the extracellular domains of all CRF2 proteins reveal primary and structural homology, their intracellular domains are very dissimilar. Nevertheless, signaling events induced through various combinations of CRF2 subunits partially overlap, leading to the induction of overlapping but cytokine-specific biological activities.

G protein-coupled receptor genes in the FANTOM2 database.

G protein-coupled receptors (GPCRs) comprise the largest family of receptor proteins in mammals and play important roles in many physiological and pathological processes. Gene expression of GPCRs is temporally and spatially regulated, and many splicing variants are also described. In many instances, different expression profiles of GPCR gene are accountable for the changes of its biological function. Therefore, it is intriguing to assess the complexity of the transcriptome of GPCRs in various mammalian organs. In this study, we took advantage of the FANTOM2 (Functional Annotation Meeting of Mouse cDNA 2) project, which aimed to collect full-length cDNAs inclusively from mouse tissues, and found 410 candidate GPCR cDNAs. Clustering of these clones into transcriptional units (TUs) reduced this number to 213. Out of these, 165 genes were represented within the known 308 GPCRs in the Mouse Genome Informatics (MGI) resource. The remaining 48 genes were new to mouse, and 14 of them had no clear mammalian ortholog. To dissect the detailed characteristics of each transcript, tissue distribution pattern and alternative splicing were also ascertained. We found many splicing variants of GPCRs that may have a relevance to disease occurrence. In addition, the difficulty in cloning tissue-specific and infrequently transcribed GPCRs is discussed further.

IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.

Typing of multiple single nucleotide polymorphisms in cytokine and receptor genes using SNaPshot.

Associations have been described between polymorphisms in cytokine genes and severity of autoimmune diseases, outcome of infectious disease, and outcome following transplantation. Many methods now exist for typing single nucleotide polymorphisms (SNPs) and these can be applied to typing cytokine gene and cytokine receptor gene variation. A system for typing multiple cytokine and receptor gene polymorphisms using a primer extension method, SNaPshot (Applied Biosystems, Foster City, CA, USA), has been assessed. The development of this methodology may enable other laboratories to type for cytokine SNPs in different populations and facilitate research into the effect of genetic polymorphism in the cytokine network in transplantation and disease.

International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature.

An update of the International Union of Pharmacology nomenclature for chemokines is outlined, defining one new receptor type, CXCR6, and disqualifying the putative receptor, CCR11.