Colony stimulating factors in the nervous system.

Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.

The Protective and Reparative Role of Colony-Stimulating Factors in the Brain with Cerebral Ischemia/Reperfusion Injury.

Stroke is a debilitating disease and has the ability to culminate in devastating clinical outcomes. Ischemic stroke followed by reperfusion entrains cerebral ischemia/reperfusion (I/R) injury, which is a complex pathological process and is associated with serious clinical manifestations. Therefore, the development of a robust and effective poststroke therapy is crucial. Granulocyte colony-stimulating factor (GCSF) and erythropoietin (EPO), originally discovered as hematopoietic growth factors, are versatile and have transcended beyond their traditional role of orchestrating the proliferation, differentiation, and survival of hematopoietic progenitors to one that fosters brain protection/neuroregeneration. The clinical indication regarding GCSF and EPO as an auspicious therapeutic strategy is conferred in a plethora of illnesses, including anemia and neutropenia. EPO and GCSF alleviate cerebral I/R injury through a multitude of mechanisms, involving antiapoptotic, anti-inflammatory, antioxidant, neurogenic, and angiogenic effects. Despite bolstering evidence from preclinical studies, the multiple brain protective modalities of GCSF and EPO failed to translate in clinical trials and thereby raises several questions. The present review comprehensively compiles and discusses key findings from in vitro, in vivo, and clinical data pertaining to the administration of EPO, GCSF, and other drugs, which alter levels of colony-stimulating factor (CSF) in the brain following cerebral I/R injury, and elaborates on the contributing factors, which led to the lost in translation of CSFs from bench to bedside. Any controversial findings are discussed to enable a clear overview of the role of EPO and GCSF as robust and effective candidates for poststroke therapy.

Role of the colony-stimulating factor (CSF)/CSF-1 receptor axis in cancer.

Cancer cells employ a variety of mechanisms to evade apoptosis and senescence. Pre-eminent among these is the aberrant co-expression of growth factors and their ligands, forming an autocrine growth loop that promotes tumour formation and progression. One growth loop whose transforming potential has been repeatedly demonstrated is the CSF-1/CSF-1R axis. Expression of CSF-1 and/or CSF-1R has been documented in a number of human malignancies, including breast, prostate and ovarian cancer and classical Hodgkin's lymphoma (cHL). This review summarizes the large body of work undertaken to study the role of this cytokine receptor system in malignant transformation. These studies have attributed a key role to the CSF-1/CSF-1R axis in supporting tumour cell survival, proliferation and enhanced motility. Moreover, increasing evidence implicates paracrine interactions between CSF-1 and its receptor in defining a tumour-permissive and immunosuppressive tumour-associated stroma. Against this background, we briefly consider the prospects for therapeutic targeting of this system in malignant disease.

Molecular Basis of Lung Tropism of Metastasis.

A predilection of metastasis to the lungs has been noted for several types of cancer. Herein, we summarize underlying mechanisms for lung tropism of metastasis. We discuss the identification of a gene signature in primary breast tumors predicting metastasis to the lungs, as well as functional validation of selected genes of the signature. We outline the contribution of pre- and metastatic niches, the role of exosomes, activation of disseminated, dormant tumor cells and selected tumor-stromal cell interactions to lung metastasis and colonization. We also refer to metastasis-mediating mechanisms based on alterations of the tumor cell cytoskeleton, as well as lung metastasis-suppressing mechanisms.

[Impact of maternal overnutrition on the periconceptional period]. / Impacto de la sobrenutrición materna sobre el periodo de periconcepción.

Overnutrition may lead to obesity. Maternal obesity may affect fertility not only via anovulation, but also through direct effects on oocytes and preimplantation embryos, indicating that the periconceptional period is sensitive to conditions of overnutrition. The periconceptional period includes from folliculogenesis to implantation. Animal model studies suggest that oocytes derived from obese females usually have a small size and mitochondrial abnormalities. These disruptions are probably induced by changes in the components of the ovarian follicular fluid. Experimental evidence also suggests that obesity may affect the microenvironment in oviducts and uterus, resulting in development of preimplantation embryos with reduced cell numbers and up-regulation of proinflammatory genes. However, further research is needed for in-depth characterization of the effects of maternal obesity during the periconceptional period.

A (selective) history of Australian involvement in cytokine biology.

This review focuses on contributions to cytokine biology made by Australians in Australia. It is clearly biased by my own experiences and selective recollections especially related to the colony-stimulating factors in which Australian involvement has been pre-eminent from discovery to clinical use. Nevertheless Australian scientists have also made profound contributions to other areas of cytokine and growth factor biology (including interferons, inflammatory cytokines, chemokines and epidermal, insulin-like and vascular endothelial growth factors) that are briefly described in this review as well as other chapters in this volume.

Maternal immune activation by poly I:C induces expression of cytokines IL-1ß and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brain.

BACKGROUND: Maternal viral infection during pregnancy is associated with an increase in the incidence of psychiatric disorders with presumed neurodevelopmental origin, including autism spectrum disorders and schizophrenia. The enhanced risk for developing mental illness appears to be caused by deleterious effects of innate immune response-associated factors on the development of the central nervous system, which predispose the offspring to pathological behaviors in adolescence and adulthood. To identify the immune response-associated soluble factors that may affect central nervous system development, we examined the effect of innate immune response activation by polyriboinosinic-polyribocytidylic acid (poly(I:C)), a synthetic analogue of viral double-stranded RNA, on the expression levels of pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors in fetal and postnatal mouse brain 6 h and 24 h after treatment. METHODS: C57BL/6J pregnant mice (gestational day 16) or newborn mice (postnatal day 4) received a single intraperitoneal injection of the synthetic analogue of viral double-stranded RNA poly(I:C) (20 mg/kg). Thirty-two immune response-associated soluble factors, including pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors, were assayed 6 h and 24 h after poly(I:C) injection using multiplexed bead-based immunoassay (Milliplex Map) and processed in a Luminex 100 IS instrument. RESULTS: Maternal exposure to poly(I:C) at gestational day 16 induced a significant increase in cytokines interleukin (IL)-1ß, IL-7 and IL-13; chemokines monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, interferon gamma-induced protein (IP)-10 and monokine induced by IFN-gamma (MIG); and in the colony stimulating factor vascular endothelial growth factor (VEGF) in the fetal brain. IL-1ß showed the highest concentration levels in fetal brains and was the only cytokine significantly up-regulated 24 h after maternal poly(I:C) injection, suggesting that IL-1ß may have a deleterious impact on central nervous system development. In contrast, poly(I:C) treatment of postnatal day 4 pups induced a pronounced rise in chemokines and colony stimulating factors in their brains instead of the pro-inflammatory cytokine IL-1ß. CONCLUSIONS: This study identified a significant increase in the concentration levels of the cytokines IL-1ß and IL-13, the chemokine MCP-1 and the colony stimulating factor VEGF in the developing central nervous system during activation of an innate immune response, suggesting that these factors are mediators of the noxious effects of maternal immune activation on central nervous system development, with potential long-lasting effects on animal behavior.

Immune factors in human embryo culture and their significance.

There is increasing evidence that human development before implantation is regulated by embryonically and maternally derived growth factors. The "regulators" of embryonic origin such as soluble human leukocyte antigen G, platelet-activating factor, Th1/Th2 cytokines, insulin-like growth factor, epidermal growth factor, transforming growth factor alpha, colony-stimulating factor, platelet-derived growth factor may be used as indicators of embryo viability and implantation potential. The data prove the influence of growth factors on the development and growth of preimplantation embryos. Though there is a lot of research in the field of biomarkers during folliculogenesis and maternal-fetal interface, only few of them deal with regulators derived from embryonic cells to the cultivation medium. The aim of our study was to summarize the research dealing with immune markers produced by embryos in vitro and to estimate their impact on the cell growth, viability and implantation potential.

[A two-phase culture system for megakaryocyte differentiation of human mobilized peripheral blood CD34+ cells].

In our study, a two-phase culture system was developed to acquire large amount of CD41+ and polyploidy cells. Human mobilized peripheral blood CD34+ (PB CD34+) cells were first cultured in expansion medium (Cocktail or CC100 medium) for 3,4,5 or 6 days, and then cultured in megakaryocytic differentiation medium containing TPO and SCF for additional 7, 8 or 9 days. Cell expansion, morphology, CD41+ cell percentage and DNA content were investigated to evaluate the protocol. The result showed that more CD41+ and polyploidy cells could be obtained following the two-phase culture with Cocktail medium than with CC100. Moreover, with 3 days expansion in Cocktail medium plus 7 days in differentiation medium, the initial CD 34+ cells obtained 16-fold expansion of CD41+ cells and 3-fold expansion of polyploidy cells, such obtained level being significantly higher than that of culturing cells with only one step in TPO or TPO+SCF. We conclude that with the two-phase culture system, PB CD34+ cells can expand and differentiate to more CD41+ and polyploidy cells than those cultured only in accordance to the one-stage culture protocol, so a new and highly efficient megakaryocyte differentiation model for megakaryocyte and platelet related researches is provided already.

Cytokines in human milk.

Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system.

Quantitative investigation of murine cytomegalovirus nucleocapsid interaction.

In this study, we quantitatively investigate the role of the M97 protein for viral morphogenesis in murine cytomegalovirus (MCMV)-infected fibroblast cells. For this purpose, a statistical analysis is performed for the spatial distribution of nuclear B-capsids (devoid of DNA, containing the scaffold) and C-capsids (filled with DNA). Cell nuclei infected with either wild-type or an M97 deletion mutant were compared. Univariate and multivariate point process characteristics (like Ripley's K-function, the L-function and the nearest neighbour distance distribution function) are investigated in order to describe and quantify the effects that the deletion of M97 causes to the process of DNA packaging into nucleocapsids. The estimation of the function L(r) -r reveals that with respect to the wild type there is an increased frequency of point pairs at a very short distance (less than approximately 100 nm) for both the B-capsids as well as for the C-capsids. For the M97 deletion mutant type this is no longer true. Here only the C-capsids show such a clustering behaviour, whereas for B-capsids it is almost nonexistant. Estimations of functionals such as the nearest neighbour distance distribution function confirmed these results. Thereby, a quantification is provided for the effect that the deletion of M97 leads to a loss of typical nucleocapsid clustering in MCMV-infected nuclei.

Hematologic disorders associated with human immunodeficiency virus and AIDS.

Nurses encounter patients with human immunodeficiency virus infection at various stages of their infection and in a variety of settings. This article focuses on the most common hematologic disorders associated with human immunodeficiency virus infection and acquired immunodeficiency syndrome, which can precipitate complications and frequently accompany hospitalization. It is important for nurses to have a solid foundation as to the cause of these disorders, their impact on quality of life and outcomes, and management strategies.

Hematopoietic colony stimulating factors in cardiovascular and pulmonary remodeling: promoters or inhibitors?

Hemopoietic colony stimulating factors (HCSFs) are naturally occurred substances that are released in response to infection or inflammation and regulate the proliferation and differentiation of hemopoietic progenitor cells. Some representative members of this peptide family induce atherogenesis through the mediation of monocyte-endothelial cell adhesive interaction and promotion of angiogenesis within the atherosclerotic plaques. HCSFs, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), also promote post-infarction cardiac remodeling though the enhanced activation and infiltration of monocytes into injured myocardial tissue and through altered equilibrium of collagen deposition/degradation. On the other hand, exogenous administration of granulocyte colony-stimulating factor (G-CSF) or eythropoietin (EPO) in patients with chronic ischemic disease or recent myocardial infarction have lead to beneficial arteriogenesis or myocardial cell regeneration, thus preventing adverse cardiac remodeling. While GM-CSF may hold therapeutic potential as an inhibitor of lung fibrogenesis, G-CSF appears to promote fibrosis in the lungs. The pathophysiological role of HCSFs also depends on the timing of their action on cardiovascular remodeling, as well as on the target progenitor hematopoietic cell. This article summarizes current knowledge about the clinical and therapeutic implications of these factors in chronic artery disease, post-infarction cardiac remodeling, chronic heart failure and in pulmonary fibrosis.

Cellular and molecular therapeutic modalities for arterial obstructive syndromes.

Arterial obstructive syndromes result in heart disease, stroke and limb loss, disability, and mortality. Currently available therapeutics for patients with these conditions are inadequate or fail in a significant number of patients. The development of novel therapies for severe coronary arterial disease (CAD), peripheral arterial disease (PAD), and cerebral vascular disease (CVD) is a major goal for modern medicine. Molecular and cell-based therapies for arterial obstructive syndromes have the potential to become clinically useful in the near future. Molecular therapy employs angiogenic proteins and genes in order to initiate the development of new blood vessels that by-pass an arterial occlusion. The induction of a collateral artery system is termed therapeutic angiogenesis or neovascularization. Proteins have been delivered either directly into the ischemic area or via a vector encoding an angiogenic gene. Both protein and gene therapies have been associated with promising preclinical and early phase human trial results in patients with PAD as well as CAD. However, to date, efficacy has not been demonstrated in placebo-controlled, large trails. Today's cell-based therapy is focused on stem cells (SCs) for the treatment of patients after acute myocardial infarction (AMI) or for patients with severe left ventricular dysfunction. Stem cells have shown to increase cardiac performance in uncontrolled, early phase human studies. This improvement is believed to have its origin in myogenesis and neovascularization. In the following review, we will cover current state of molecular- and cellular-based treatments for PAD and CAD that have reached the clinical arena.

Cytokines, chemokines and growth factors in endometrium related to implantation.

The complexity of the events of embryo implantation and placentation is exemplified by the number and range of cytokines with demonstrated roles in these processes. Disturbance of the normal expression or action of these cytokines results in complete or partial failure of implantation and abnormal placental formation in mice or humans. Of known importance are members of the gp130 family such as interleukin-11 (IL-11) and leukaemia inhibitory factor (LIF), the transforming growth factor beta (TGFbeta) superfamily including the activins, the colony-stimulating factors (CSF), the IL-1 system and IL-15 system. New data are also emerging for roles for a number of chemokines (chemoattractive cytokines) both in recruiting specific cohorts of leukocytes to implantation sites and in trophoblast differentiation and trafficking. This review focuses on those cytokines and chemokines whose expression pattern in the human endometrium is consistent with a potential role in implantation and placentation and for which some relevant actions are known. It examines what is known of their regulation and action along with alterations in clinically relevant situations.

Regulation of myeloid development and function by colony stimulating factors.

The colony-stimulating factors (CSFs) are a group of cytokines central to the hematopoiesis of blood cells, the modulation of their functional responses, as well as the maintenance of homeostasis and overall immune competence. This group consists of the macrophage-CSF (M-CSF), granulocyte-CSF (G-CSF), granulocyte/macrophage-CSF (GM-CSF), and multi-CSF (IL-3). M-CSF and G-CSF are relatively lineage-specific, having a role in the proliferation, differentiation, and survival of macrophages, neutrophils, and their precursors. In contrast, GM-CSF and multi-CSF function at earlier stages of lineage commitment regulating the expansion and maturation of primitive hematopoietic progenitors. Colony stimulating factor production and degradation are strictly controlled, thus allowing for effective modulation of their biological functions in steady-state conditions as well as under periods of stress. Moreover, the mechanisms behind their expression and that of their cognate receptors ensures that their actions are tightly coordinated, within the context of a network of complex but finely tuned regulatory pathways derived from a variety of local and endocrine hematopoietic regulators. In this review we present some of the most salient information on CSF biology collected over the last three decades. We examine the gene and protein structure of each of the four CSFs and their corresponding receptors, and consider the main determinants behind their biological activities. The components responsible for their functional redundancy as well as the mechanisms that mediate their specificity are also discussed. Although most of available knowledge about CSFs is on human and mouse CSFs, an attempt was made to integrate recent findings in other systems in order to highlight a more widespread role for CSFs throughout evolution.