Current Pharmaceutical Design - Volume 12, Issue 24, 2006

In recent years, the knowledge on cytokines has advanced and even if new data are continuously added, we would contribute throwing light upon the multiple functions that these molecules can accomplish. As documented by the contributions here reported, these molecules are described as cytokine-like and cytokines in invertebrates and vertebrates, respectively. Actually, fish represent the first group in which cytokine genes are found. The collected reviews regarding protozoa, invertebrates, vertebrates including man, report on biological activities of these versatile molecules that range over many fields. Cytokine-like and cytokines play several important roles such as chemical secretion (pheromones), development, immune and neuroendocrine responses, wound repair, aging, longevity and so on. Taken together, the reviewed data confirm the surprising similarity between molecules and processes in invertebrates and vertebrates and suggest that basic common features of fundamental biological events are conserved and extended across diverse species, tissues and developmental phases, supporting the general idea that an increasing number of early acquisitions during metazoan evolution are also common in higher vertebrates. In accordance with these concepts we propose as first review of the issue a speculation about phylogeny that could be useful to set the general problem of conservation of molecules and their functioning in the evolutional background. Lanzavecchia's paper [1], starting from historical data, underlines that on the whole biological evolution appears as a series of modulations more or less accentuated by a grouping of genetic information that are maintained rather constant along all the branches of the phylogenetic tree. The studies on the genomes of diverse animals confirm the existence of a relevant molecular conservation and this fundamental conservation of the general genetic patrimony of the living organisms justifies the use of diverse animal forms for the study and comprehension of general biological phenomena, potentially relevant for human health. In the second article, Luporini and coworkers [2] provide data on structure of the Euplotes raikovi, Euplotes octocarinatus, and Euplotes nobilii pheromone family members. These studies have expanded the knowledge of the biological and evolutionary significance of these ancient, cell type-specific signal proteins. Identified and for a long time studied only for their paracrine mating inducing activity, pheromones have now revealed a more universal and primordial function such as autocrine cell stimulation for the vegetative growth revealing intriguing similarities of structure and cross-reactions with members of cytokines evolved by more advanced multicellular organisms. The paper of Franchini et al. [3] outlines the presence and function of TGF-β and PDGF family members in invertebrates, stressing the early appearance of these molecules in evolution. These molecules play an important role in development, in immune and neuroendocrine responses and in wound repair by activating classical transduction pathways. Grimaldi and coworkers' paper [4] focuses on the comparison of angiogenic process in vertebrates and hirudineans subjected to surgical explant or cytokine treatment. The reviewed data confirm the surprising similarities between leech and vertebrate processes in wound healing and suggest that basic common events such as antigenic expressions of endothelial and hemopoietic cells, cytokine secretion and regulation as well as extracellular matrix interactions, are conserved and extended across diverse species, tissues and developmental phases. The article of Salzet et al. [5] emphasizes the different immunodefense strategies that adaptation undertakes during the course of evolution of two classes of annelids i.e. oligochaetes and achaetes. Innate immunity plays a major role as a first defense against microbes. Effectors of the innate response include pattern recognition receptors (PRR), phagocytic cells, proteolytic cascades and peptides/proteins with antimicrobial properties. Each element of these events has been well studied in vertebrates and in some invertebrates such as annelids. From these different researches, it appears that mammalian innate immunity could be considered as a mosaic of invertebrate immune responses. Annelids belonging to the lophotrochozoans' group are primitive coelomates that possess specially developed cellular immunity against pathogens including phagocytosis, encapsulation and spontaneous cytotoxicity of coelomocytes against allogenic or xenogenic cells. They have also developed an important humoral immunity that is based on antimicrobial, hemolytic and clotting properties of their body fluid.....

After a general view of the actual situation of the phylogenetic relationships between the diverse animals and thus having traced the fundamental elements of an essentially phylogenetic classification, several themes that emerge from this initial analysis have been developed. For instance one of the fundamental problems is about homologous genes shared by the protostomes and deuterostomes and attributed back to that hypothetical group of the primitive bilaterians, the Urbilateria, "reconstructed" from genetic analysis. The analyzed genes are essentially of a regulatory type, thus a remarkable conservation of functions seems to exist. This fundamental conservation of the general genetic patrimony of the living organisms, within an overall picture which includes an infinite gamma of structural and functional modulations of the single genes, and a vast gamma of temporal and spatial modulations of regulation of the genic activity, justifies the use of diverse animal forms for the study and comprehension of general biological phenomena, potentially relevant for human health.

In association with their mechanisms of self/non-self recognition (known as mating type systems), ciliates synthesize and constitutively secrete cell type-specific proteins into their extracellular medium. These proteins, designated as pheromones, have been isolated from species of Euplotes and shown to be members of families of structurally homologous molecules, all rich in intra-chain disulfide bonds and organized exclusively in helical conformation. Due to their similar architectures, they can interact with their membrane receptors in competition with one another and bind effectively to their cells of origin in autocrine fashion, or to other co-specific cells in paracrine fashion. In the former case, they promote the vegetative cell growth; in the latter, they induce cells to temporarily arrest their growth stage and shift to a mating (sexual) stage. These varied, context-dependent activities of ciliate pheromones imply an early evolution of basic properties of animal growth factors and cytokines in the unicellular eukaryotes.

The review outlines the presence and function of TGF-β and PDGF family members in invertebrates. TGF-β and PDGF play an important role in development, in immune and neuroendocrine responses and in the wound repair by activating the classical transduction pathways. Generally speaking, these cytokines appear very early in evolution and conserve their functions.

The angiogenic process in vertebrates and hirudineans has been compared. The leech Hirudo medicinalis, subjected to an angiogenic stimulus (surgical explant or cytokine treatment) responds, as a vertebrate, with the formation of an extensive network of new vessels accompanied by the production of circulating cells. The reviewed data confirm the surprising similarity between hirudinean and vertebrate processes in wound healing, and suggest that basic common events such as antigenic expressions of endothelial and hemopoietic cells, cytokine secretion and regulation as well as extracellular matrix interactions, are conserved and extended across diverse species, tissues and developmental phases.

Innate immunity plays a major role as a first defense against microbes. Effectors of the innate response include pattern recognition receptors (PRR), phagocytic cells, proteolytic cascades and peptides/proteins with antimicrobial properties. Each element of these events has been well studied in vertebrates and in some invertebrates such as annelids. From these different researches, it appears that mammalian innate immunity could be considered as a mosaic of invertebrate immune responses. Annelids belonging to the lophotrochozoans' group are primitive coelomates that possess specially developed cellular immunity against pathogens including phagocytosis, encapsulation and spontaneous cytotoxicity of coelomocytes against allogenic or xenogenic cells. They have also developed an important humoral immunity that is based on antimicrobial, hemolytic and clotting properties of their body fluid. In the present review, we will emphasize the different immunodefense strategies that adaptation has taken during the course of evolution of two classes of annelids i.e. oligochaetes and achaetes.

Complex immune systems require complex regulatory mechanisms. Whilst the control of innate and inflammatory responses is likely to be ancient in origin, and potentially ubiquitous in the animal kingdom, clearly the evolution of an adaptive immune system in vertebrates is likely to coincide with new regulatory mechanisms and molecules. Key amongst these is the cytokine network, well characterised in mammals and becoming increasingly well characterised in fish and birds. This article will review our current understanding of which components of this network are crucial for adaptive immunity and evolved early, being present from fish to mammals. It will also consider which components of this network potentially evolved later (after the fish-tetrapod divergence) leading to unique cytokine genes in particular vertebrate groups.

It appears evident that teleost fish are at present the vertebrate group in which, excluding mammals, most information on the immune system is available. However, despite the great impetus on the discovery of genes homologous to mammalian immunomodulatory molecules, the knowledge on biological activities exerted by cytokines is meager. This review reports the present knowledge on the biological activities of cytokine-like and cytokines in invertebrates and coldblooded vertebrates.

In recent years the knowledge of avian cytokines has advanced and new data are continuously added. Nevertheless, some discontinuities persist and the correlations between molecular and functional levels are not completely clear. Most of the studies are focused on chicken, and comparative aspects with other avian groups are limited. The existence of T1 and T3 avian cytokines was assessed long ago and the recent relevant demonstration of the existence of T2 cytokines in birds is a further step in depicting a more complete view on avian immunology. The progressive knowledge of avian cytokines can hopefully help in developing new strategies in prophylaxis and therapy of avian diseases, not always completely controlled due to the emergence of more pathogenic strains.

The intricate interplay between the endothelium and immune cells has been well recognized in the context of immune responses. However, the fact that this inter-relation extends well beyond immune regulation is becoming increasingly recognized, with particular regards to the influence of the immune system on the essential endothelial process of angiogenesis, where the contribution of cytokines drives the angiogenic process. As angiogenesis is an important component of numerous pathological states, among these chronic inflammatory conditions and cancer, understanding the role of cytokines and chemokines in guiding new vessel formation provides key insight into novel therapeutic modalities. Here we review the actions of principal cytokines and chemokines on the angiogenic process and discuss how both can be considered potential pharmaceutical targets or pharmaceuticals themselves for modulation of angiogenesis in chronic inflammation associated with cancer, rheumatoid arthritis and other inflammatory diseases.

A number of in vitro studies have implicated protein kinase Cδ(PKCδ) and PKCε in the regulation of the immune system. In recent years, this has been convincingly demonstrated in mice deficient for PKCδ and PKCε. The reported phenotypes for these transgenic mice indicate that PKCδ suppresses immunoresponsiveness and inhibits the proliferation of B-lymphocytes, while PKCε is required for macrophages to mount an effective immune response to bacterial pathogens. In either case, these isoenzymes appear to cooperate in fine-tuning certain immunoreactions by either suppressing (PKCδ) or stimulating (PKCε) the transcription of various cytokines. This review will compare and contrast the structures of these two nPKC isoenzymes and their respective roles in the modulation of cytokine production and various other cellular processes, such as growth, differentiation, apoptosis, and tumor suppression.

How cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CB1 is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoietic colony formation in which cannabinoids have demonstrated a clear role as important modulators.

The so-called demographic transition has changed the age structure of the population worldwide, with profound effects on societal organization. The growing number and percentage of old and very old people has compelled the scientific community to focus on age related diseases and peculiar consequences of aging itself such as disability and frailty. Understanding the pathophysiology of frailty, a syndrome characterized by a reduced functional reserve and impaired adaptive capacity that results from cumulative declines of multiple subsystems, and causes increased vulnerability to adverse outcomes, is a major topic in aging research. Aging processes induce multiple changes in the hormones network (menopause, andropause, somatopause and adrenopause), in the immune system, and can modulate their efficiency and effectiveness in determining a response to stressors. These triggering events can unmask frailty in older people. Starting from these assumptions, we analyzed the relationship of the endocrine and immune networks in aging and in the different domains that are characteristically associated with the frailty syndrome, such as disability and sarcopenia, as well as in diseases related to aging such as Alzheimer's dementia and Congestive Heart Failure.

In this article we summarise present knowledge on the role of pro-inflammatory cytokines on chronic inflammation leading to organismal aging, a phenomenon we proposed to call "inflamm-aging". In particular, we review genetic data regarding polymorphisms of genes encoding for cytokines and proteins involved in natural immunity (such as Tolllike Receptors and Heat Shock Proteins) obtained from large population studies including young, old and very old people in good health status or affected by age-related diseases such as Alzheimer's Disease and Type II Diabetes. On the whole, despite some controversial results, the available data are in favour of the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity. Further, we present a possible hypothesis to reconcile energetic dysfunction, including mitochondria, and inflamm-aging. New perspectives for future studies, including phylogenetic studies in animal models and in silico studies on mathematical and bioinformatic models inspired by the systems biology approach, are also proposed.