Cytokine Biology Research Articles

Basophil and Mast Cell Lineages In Vitro and In Vivo

VER SINCE Paul Ehrlich’s discovery that granuleE laden cells (“mastzellen”) in the frog mesentery, originally observed by von Recklinghausen, possessed metachromatic staining properties,’” cells in the basophil and mast cell lineages have been the subject of much scrutiny. The description by dermatologists at the turn of the century of the condition known as urticaria pigmentosa, involving mast cell infiltration in the skin and other organs?4 and subsequent findings that mast cells contain various preformed mediators of inflammation such as histamine: led gradually to a widespread fascination with the role of these cells in biologic processes. In parallel with these observations were descriptions by Ehrlich’ and later by hematologists of the presence of a blood-borne metachromatic, histamine-producing granulocyte, the basophil, significantly prominent in a number of myeloproliferative diseases, especially in chronic myeloid leukemia: Historically, because of their common metachromatic staining properties, the basophil and the mast cell have been thought to be intimately related in terms of hematopoietic lineage, and the literature is indeed replete with this assumption. The mast cell in the tissue and the basophil in the blood have, however, not been proven to be derived from a common stem cell in either animals or humans; moreover, there appears to be an inverse relationship between the presence of basophils or mast cells as the prominent representative of a metachromatic cell among various species.’ This review will focus on the ontogeny of basophils and mast cells, exploring knowledge in this field as it relates to cytokine biology, allergy and inflammation, and clinical hematology. The extensive literature on the biology of the mast cell in various processes, such as wound healing, repair, and fibrosis or on basophil and mast cell secretory function, will be touched upon only briefly within the scope of this review. MURINE MAST CELL GROWTH AND DIFFERENTIATION

Cytokines in viral diseases

As in many other areas of cytokine biology, recent studies of the role of cytokines in viral disease reveal numerous complex interactions that in many instances may contribute directly to the development of pathology. For example, data from the rapidly evolving field of human retrovirology has shown that these viruses, as well as inducing the expression of many cellular cytokine genes, can be activated from latency and driven into replication/expression by the very same cytokines. The continuing rapid expansion of knowledge in the cytokine area augers well for eventual development of novel antiviral therapeutic strategies based on manipulation of the cytokine network.

Cytokine biology. Implications for transfusion medicine

The development and widespread availability of recombinant products will effect blood centers through reduced product use, replacement of current products, and novel applications of new products. The greatest amount of clinical experience to date has dealt with the use of recombinant human erythropoietin (r-HuEPO) in the treatment of anemia in end-stage renal failure. Data also support its use in anemia associated with acquired immune deficiency syndrome (AIDS), cancer, and chronic inflammatory diseases. This article will focus on the effect of erythropoietin on the demand for erythrocyte use.

Materno--foeto--placental interactions

21–23 May 1990Synopsis of a Conference sponsored by the National Institute of Child Health and Human Development, Bethesda, MD, USAThis Conference was sponsored by NICHD to facilitate progress in relating basic advances in immunology, molecular biology of the MHC (major histocompatibility complex) and cytokine biology to reproductive events. Maternal mechanisms that prevent 'rejection' of the foetus as a foreign graft are not yet completely understood. Indeed, products of the maternal immune system may actually facilitate the growth and healthy development of the foetus. The goal of NICHD was to promote examination and integration of the recent proliferation of basic data with respect to the role of rejection and facilitation in infertility and both early and late pregnancy pathology.NICHD invited 5 scientists to attend a planning meeting in Bethesda, Maryland, in December, 1989. These scientists, who became the moderators at the conference as listed below, devoted their expertise

Cytokines of the Lung

Communication between cells determines the steady-state composition of the lung in health and becomes a critical determinant of outcome in pathologic processes resulting in anatomic remodeling. This review presents the evolving concepts of the biology of cytokines (also known as peptide growth factors or biological response modifiers) in maintaining normal tissue growth and homeostasis. How these extracellular signaling proteins are involved in such pathologic disorders as spontaneous pulmonary fibrosis, sarcoidosis, pneumoconiosis, and the evolution and recovery from acute lung injury is also discussed. During the past decade the cytokines have come to the fore as important multifunctional mediators of cell behavior and cell-cell communication. A wide range of cellular responses are influenced or triggered when cytokines interact with cells. These include mitosis, chemotaxis, angiogenesis, cytoskeleton arrangement, immunomodulation, and extracellular matrix production. Cytokines influence cell behavior by binding to specific high affinity surface receptors on target cells. These receptors are linked in turn at the cell membrane to a complex array of intracellular signaling pathways. Individual cytokines may inhibit as well as promote cellular functions such as mitosis and thereby play a critical role in homeostasis of normal tissue elements. Hence, cytokines are intimately involved in normal tissue homeostasis as well as in processes eventuating in growth and remodeling. All cells produce and secrete cytokines at some time during their life. Each cytokine is capable of modulating more than one cellular function. Although produced by a variety of cell types, the triggers that induce a specific cytokine to be produced differ between cells. Many of the cytokines share regions of homologous nucleic acid sequences, suggesting that they are members of larger gene families. Given that tissues and cells are exposed to complex cytokine mixtures rather than to individual cytokines, recent attention has turned to understanding how cytokines interact. The combined effects of cytokine mixtures have proved to be both complex and unpredictable based on knowledge of the separate actions of the individual cytokines involved. In studies of the role of cytokines in lung disease, early research attention has focused on those cytokines released by alveolar macrophages (the so-called macrophage-derived growth factors). However, structural cells as well as immune effector cells of the lung are capable of cytokine production and release. The cytokines receiving the most attention to date in relation to pulmonary diseases include platelet-derived growth factor (PDGF), interleukin-1 (IL-1), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), insulinlike growth factor I (IGF-I), and, most recently, interleukin-6 (IL-6).(ABSTRACT TRUNCATED AT 400 WORDS)

Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF)

Interleukin 1 (IL 1), IL 6, and tumor necrosis factor (TNF) are typical examples of multifunctional cytokines involved in the regulation of the immune response, hematopoiesis, and inflammation. Their functions are widely overlapping but each shows its own characteristic properties. IL 6 was originally identified as a B cell differentiation factor, and thus one of the major functions of IL 6 is antibody induction. Transgenic mice have provided much needed information on the pathophysiological role of cytokines. With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis. The cis-regulatory elements and trans-acting nuclear factor (or factors) for the IL 6 expression (NF-IL 6) have been identified. NF-IL 6 was shown to be a member of a C/EBP family, and the possible involvement of NF-IL 6 not only in the IL 6 regulation but also in the induction of various acute phase proteins was also observed. The findings suggest the presence of a positive regulatory loop in acute-phase reaction. IL 1 receptor belongs to an Ig superfamily, but the IL 6 receptor is a member of a newly identified cytokine receptor family. The IL 6 receptor system was shown to be composed of a ligand binding chain and a signal-transducing molecule. IL 6 was found to trigger the association of these two polypeptide chains. This unique mechanism may be applied to other cytokine receptor systems.

Cytokines of the Lung

Communication between cells determines the steady-state composition of the lung in health and becomes a critical determinant of outcome in pathologic processes resulting in anatomic remodeling. This review presents the evolving concepts of the biology of cytokines (also known as peptide growth factors or biological response modifiers) in maintaining normal tissue growth and homeostasis. How these extracellular signaling proteins are involved in such pathologic disorders as spontaneous pulmonary fibrosis, sarcoidosis, pneumoconiosis, and the evolution and recovery from acute lung injury is also discussed. During the past decade the cytokines have come to the fore as important multifunctional mediators of cell behavior and cell-cell communication. A wide range of cellular responses are influenced or triggered when cytokines interact with cells. These include mitosis, chemotaxis, angiogenesis, cytoskeleton arrangement, immunomodulation, and extracellular matrix production. Cytokines influence cell behavior by binding to specific high affinity surface receptors on target cells. These receptors are linked in turn at the cell membrane to a complex array of intracellular signaling pathways. Individual cytokines may inhibit as well as promote cellular functions such as mitosis and thereby play a critical role in homeostasis of normal tissue elements. Hence, cytokines are intimately involved in normal tissue homeostasis as well as in processes eventuating in growth and remodeling. All cells produce and secrete cytokines at some time during their life. Each cytokine is capable of modulating more than one cellular function. Although produced by a variety of cell types, the triggers that induce a specific cytokine to be produced differ between cells. Many of the cytokines share regions of homologous nucleic acid sequences, suggesting that they are members of larger gene families. Given that tissues and cells are exposed to complex cytokine mixtures rather than to individual cytokines, recent attention has turned to understanding how cytokines interact. The combined effects of cytokine mixtures have proved to be both complex and unpredictable based on knowledge of the separate actions of the individual cytokines involved. In studies of the role of cytokines in lung disease, early research attention has focused on those cytokines released by alveolar macrophages (the so-called macrophage-derived growth factors). However, structural cells as well as immune effector cells of the lung are capable of cytokine production and release. The cytokines receiving the most attention to date in relation to pulmonary diseases include platelet-derived growth factor (PDGF), interleukin-1 (IL-1), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), insulinlike growth factor I (IGF-I), and, most recently, interleukin-6 (IL-6).(ABSTRACT TRUNCATED AT 400 WORDS)

A new mitogen for tumor infiltrating lymphocytes (TILS) derived from a tumor cell line: Beverly S. Packard. Division of Cytokine Biology, CBER, FDA, Bethesda, MD. 20892

This chapter focuses on the possible mechanism of natural killer (NK) cell-mediated cytotoxicity (CMC) in which the soluble cytotoxic mediators natural killer cytotoxic factors (NKCF) are implicated. The chapter investigates the characteristics of the NK cytotoxic system and its relationship to cytotoxic T lymphocytes (CTL)-mediated cytotoxicity. Studies proposed in the chapter for the NK cytotoxic system may be applicable to other cytotoxic systems mediated by non NK effector cells. The availability of recombinant, purified lymphotoxin (LT) and tumor necrosis factor (TNF) and the possible availability of recombinant cytolysin or perforin in conjunction with NKCF enable establishing the relationship among various cytotoxins and their role in the mechanism of cell-mediated cytotoxicity. It is reasonable to develop approaches that can either enhance susceptibility of tumor cells to lysis by NK cells or NKCF or to consider treatments that can restore functional NK activity where it is defective.

FDA Workshop Explores Growth Factor Uses

THE Food and Drug Administration's (FDA) Division of Cytokine Biology recently held a workshop to explore the clinical uses of hematopoietic growth factors (HGF), the hormonelike proteins that control the development and differentiation of blood cells (See From the FDA , page 1296). Nine potential human HGFs have been identified, their genes cloned, and their chromosomal locations pinpointed. They have been produced in quantity by recombinant DNA methods. In the past 2 years, several HGFs have been evaluated in clinical trials. Some of the investigators conducting these trials presented the emerging applications for the agents. Cancer Therapy.— Jordan Gutterman, MD, of the M. D. Anderson Cancer Center, Houston, Tex, chaired a session on the use of two HGFs, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF), as adjuvants in cancer chemotherapy. Gutterman said that early results of several studies indicate that the agents have reduced periods of severe neutropenia