SurveyThe multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1
Section snippets
Introduction – discovery of GDF-15
Growth/differentiation factor-15 (GDF-15) was discovered and cloned as a divergent member of the TGF-β superfamily in the late 1990s independently in at least seven different laboratories. Names were given based on relationship to TGF-β members or different cloning strategies applied. Using a subtraction cloning approach designed to identify genes related to macrophage activation, Bootcov et al. [1] identified macrophage inhibitory cytokine-1 (MIC-1). They found MIC-1 to be upregulated in
Gene structure, regulation of expression and tissue distribution
Initial analyses of the rat, mouse and human GDF-15 genes revealed that they are composed of two exons, and contain one single intron that interrupts the coding sequences at identical positions within the pre-pro-domain of the corresponding proteins (Fig. 1) [3], [6]. The predicted proteins contain the structural hallmarks of members of the TGF-β family, i.e. the seven conserved carboxy-terminal cysteine residues that form a cysteine knot (Fig. 1) [3], [4]. Lawton et al. [3] also identified, in
GDF-15 signaling
The receptor(s) for GDF-15 have not been unequivocally identified. Several studies have suggested that GDF-15 might signal through canonical TGF-β receptors and signaling (i.e. Smad) pathways. Using cardiomyocytes transformed with SMAD-decoy oligonucleotides, Heger et al. [18] observed a blockade of GDF-15 mediated protein synthesis and hypertrophy. In addition, also inhibitors of PI3-kinase and ERK blocked the hypertrophic growth response to GDF-15. The Breit group [19] reported that the
Inflammation
Roles of GDF-15/MIC-1 in inflammation became already apparent through an initial series of studies on its autocrine regulation in macrophages, where it serves to limit the later phases of activation [1], [9]. Later, animal models of myocardial infarction, atherosclerosis and rheumatoid arthritis revealed its broad anti-inflammatory and immunosuppressive properties on a systemic level [21]. For example, in the infarcted heart GDF-15 acts as an anti-inflammatory cytokine by repressing leukocyte
Vascular functions
A role and signaling mechanisms of GDF-15 in angiogenesis have recently emerged [26]. GDF-15 impairs in vitro angiogenesis by blocking connective tissue growth factor 2 (CCN-2) mediated tube formation in human umbilical vein endothelial (HUVEC) cells and does so by inhibiting the CCN-2-dependent activation of focal adhesion kinase and subsequent decrease in alpha(V) β(3) integrin clustering. In the same vein, GDF-15, in combination with BMP-2, has been shown to mediate the inhibition of
Hematology
Although the complete scenario of GDF-15 and its implications in erythropoiesis is still not fully understood, it seems that its synthesis by erythroid progenitor cells is widely accepted [43]. Production and secretion of GDF-15 by erythroid cells is dependent on erythropoietin and the type 2 transferrin receptor. Levels of circulating GDF-15 can be induced by pathophysiological changes in iron availability [44]. However, iron deficiency in blood donation volunteers has been reported not to be
Metabolism
GDF-15 is implicated in many aspects of metabolic disorders, as e.g. obesity, insulin resistance, anorexia and weight loss. GDF-15 is synthesized and released into the circulation by many types of cancer cells. For example, in patients with advanced prostate cancer GDF-15 levels in serum and weight loss are directly correlated [19]. Grafting prostate tumors to mice, infusing GDF-15, or overexpressing GDF-15 raises levels of circulating GDF-15 and causes reductions in food intake, weight, and
Gastrointestinal system
Initial studies on GDF-15 already indicated that this cytokine is extremely abundant in the adult liver [54]. Northern analysis revealed that GDF-15 expression was rapidly upregulated following treatment of two hepatocyte cell lines with carbon tetrachloride or heat shock induced GDF-15 mRNA expression, indicating that induction of GDF-15 may occur in the absence of inflammatory cells. Injury mediated GDF-15 induction was independent of tumor necrosis factor and p53, as revealed by analysis of
Respiratory system
GDF-15 is expressed in pulmonary bronchial and bronchiolar epithelia (Fig. 2g and h) [6]. Cigarette smoke exposure has been reported to upregulate GDF-15 protein expression in airway epithelium, most notably in ciliated cells [60]. GDF-15, in turn, subsequently activates the PI3K pathway to promote mucin overexpression, a hallmark of chronic obstructive pulmonary disease.
As for acute coronary syndrome or heart failure, GDF-15 provides independent prognostic information in patients with acute
Kidney
In situ hybridization of GDF-15 mRNA in the kidney revealed prominent expression in the nephron S3 segment and collecting ducts (Fig. 3a) [6], which, for many years, has not been addressed in functional terms. With regard to collecting ducts, GDF-15 is apparently an important determinant of duct lengthening during adaptation to metabolic acidosis, as acid-secreting intercalated cells proliferate [63]. Acid secretory A intercalated cells express apical H(+)-ATPases and basolateral bicarbonate
Skeletal system
Osteocytes are the most abundant cells in bone. They secrete GDF-15 under hypoxic conditions in vitro and in vivo [80], [81]. GDF-15 promotes osteoclastic differentiation in cell culture and in vivo; its immunoneutralisation has been shown to prevent bone loss through inhibiting osteoclastic activation in a mouse model with ligated femoral artery [80]. Secondary tumors originating from prostate and other carcinomas may affect remodeling of bone tissue and induce both osteolytic and
Nervous system
Early studies in our laboratory on GDF-15 in the nervous system had shown that GDF-15 is widely distributed in the central (CNS) and peripheral nervous system (PNS; [84]). Using qRT-PCR and Western blotting, low levels (when compared to liver, lung, kidney) of GDF-15 mRNA and protein are found in all regions of the unlesioned rat and mouse CNS, in peripheral nerves, in isolated astrocytes and dorsal root ganglion cells (DRGs). Highest levels of GDF-15 mRNA and protein were found to be expressed
Skin
GDF-15 has been implicated in the regulation of keratinocyte differentiation [93]. siRNA-mediated knockdown of endogenous GDF-15 in the keratinocyte cell line HaCaT has been shown to permit cell growth and inhibit expression of the differentiation markers keratin 10 and involucrin in response to differentiation stimuli. Dermal fibroblasts have been suggested to represent another source of GDF-15 in skin: both GDF-15/MIC-1 mRNA and protein are induced in cultured human dermal fibroblasts by
Cancer
Growth-stimulatory secreted peptide growth factors, cytokines and hormones are often found to be overexpressed in tumor cells. Increased circulating levels of these proteins can not only be exploited for cancer diagnosis and prognosis; the protein itself, expressed by the tumor cells may also serve as a target for interventional therapies. GDF-15/MIC-1 is among the genes that encode proteins with high levels of tumor-associated expression [99]. Early in the research history of GDF-15
GDF-15 in submammalian species
Information on GDF-15 in submammalian species is scarce. Its full-length cDNA has been cloned from the Japanese flounder [119]: The deduced amino acid sequence exhibited low identity (<30%) with GDF-15 from mammals GDF-15. GDF-15 mRNA was prominently upregulated in fish liver following injection of formalin-inactivated Streptococcus iniae.
In a monotreme, the male platypus, GDF-15 has been identified in the venom that these animals secrete during the breeding season [120].
Conclusions
The past decade has seen significant advances in recognizing many novel functions of GDF-15 in vitro and in vivo. Collectively, GDF-15 resembles other members of the TGF-β superfamily in many respects, most notably its ubiquitous expression, roles in the regulation of cell proliferation, migration, maintenance, and homeostasis. Similar to other TGF-βs GDF-15 is a typical contextually acting growth factor. Impressive advances have been made in the understanding of implications of GDF-15/MIC-1 in
Acknowledgements
We thank Dr. Andreas Schober for work on the figures, Ms Hummel for secretarial help, and the German Research Foundation (DFG) for supporting our work on GDF-15. We apologize for publications not cited due to space limitations or an oversight on our part.
Klaus Unsicker, born 1942, is a Guest and Emeritus Professor at the University of Freiburg, Faculty of Medicine (Germany), where he maintains a medium-sized laboratory with three graduate students and two postdoctoral fellows. Postdoctoral training: Klaus Unsicker did his postdoctoral training at the Universities of Kiel, Lund and Melbourne from 1970 to 1975. Academic appointments: Klaus Unsicker has been Associate Professor of Anatomy at the University of Kiel (1976–1977) and Full Professor of
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Klaus Unsicker, born 1942, is a Guest and Emeritus Professor at the University of Freiburg, Faculty of Medicine (Germany), where he maintains a medium-sized laboratory with three graduate students and two postdoctoral fellows. Postdoctoral training: Klaus Unsicker did his postdoctoral training at the Universities of Kiel, Lund and Melbourne from 1970 to 1975. Academic appointments: Klaus Unsicker has been Associate Professor of Anatomy at the University of Kiel (1976–1977) and Full Professor of Anatomy and chair of Neuroanatomy at the Universities of Marburg and Heidelberg from 1978 to 2007. He was Visiting Professor at UCSD (1983–1984), NIH/NCI (1989–1990), and University of Helsinki (2006). Klaus Unsicker has held numerous positions, nationally and internationally, on the boards of grant giving bodies, study sections, evaluation committees, scientific advisory boards, and as a coordinator of collaborative research initiatives. Currently he serves as the chairman of the scientific advisory board of the University of Helsinki. He maintains editorial responsibilities including the chief editorship of Cell & Tissue Research. Awards and honors: Klaus Unsicker has received numerous research prizes and honorary memberships including the Research Medal of the University of Helsinki, the Max-Planck Research Prize for International Collaboration, the Aschoff Medal of the Medical Faculty of the University of Freiburg, a honorary doctorship of the University of Marburg and the honorary membership of the Romanian Society for Cell Biology. He is a member of the German Academy of Sciences Leopoldina. Major research interest: The group of Klaus Unsicker works in three fields, first, on the development of the neural crest, with a focus on the determination of derivatives of the sympatho-adrenal cell lineage, second on neural functions of GDF-15, a member of the TGF-β superfamily, and, third, FGF signaling in adult neurogenesis and major depression. For details, please visit portal.uni-freiburg.de/anatomie2/staff/unsicker.
Björn Spittau, born 1979, is a research group leader at the Institute of Anatomy and Cell Biology, Department of Molecular Embryology at the Albert-Ludwigs-University of Freiburg (Germany). He obtained his M.D. degree at the Georg-August-Universtiyof Göttingen. Postdoctoral training: Björn Spittau underwent postdoctoral training in the Department of Neuroanatomy (University of Göttingen) from 2006 to 2008 and from 2008 onwards at the Institute of Anatomy and Cell Biology (University of Freiburg). Major research interest: His research interests are focused on the neuroinflammation in animal models for Parkinson's disease (PD) and the contribution of microglia to neurodegeneration and neuroregeneration. Moreover, his research is devoted to understand the mechanisms by which immunomodulatory factors, such as TGF-beta, regulate microglia functions under physiological and pathological conditions.
Kerstin Krieglstein, Professor at the University of Freiburg, Faculty of Medicine (Germany). She is a specialist in the field of developmental neurobiology. Kerstin Krieglstein is head of Molecular Embryology at the University of Freiburg. Postdoctoral training: Kerstin Krieglstein underwent postdoctoral training at the University of California, Irvine (Department of Molecular Biology and Biochemistry) from 1990 to 1992, and at the Institute of Anatomy and Cell Biology in Marburg and Heidelberg from 1992 to 1997, before receiving a Heisenberg fellowship in 1997. Academic appointments: Krieglstein had appointments as associated professor at the University of Saarland, Homburg from 1999 to 2001,and full professor and chair of Neuroanatomy at the University of Göttingen from 2001 to 2007. In 2007, she was appointed as head of the Department of Molecular Embryology at the University of Freiburg. Awards and honors: Krieglstein is member of the German Academy of Sciences Leopoldina (since 2007) and fellow of the Freiburg Institute of Advanced Studies (FRIAS) from 2010 to 2012. Major research interest: The group of Professor Krieglstein is particularly interested in role of extrinsic signaling molecules during nervous system development, primarily for specification of distinct neuronal phenotypes, regulation of neuron survival and death and the establishment of neuronal circuits. Key research activities are in the fields of growth factor and cytokine signaling, developmental regulatory networks and paracrine mechanisms in PNS and CNS.