Cytokine & Growth Factor

The role of the IL-33/ST2 axis in autoimmune disorders: Friend or Foe? Publication date: Available online 3 April 2019 Source: Cytokine & Growth Factor Reviews Author(s): Xiuxing Liu, Yichen Xiao, Yuan Pan, Li He, Song Guo Zheng, Su Wenru Abstract Autoimmune diseases (ADs), which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T effector (Th)1/Th17 cells and T regulatory cells. Interleukin (IL)-33, a member of the IL-1 family, induces inflammatory disease development by mediating type 2 immune responses. Recently, IL-33/ST2 axis was reported to induce autoimmunity involving Th1 and Th17 cells. In this review, we focus on the expression, regulation and function of IL-33/ST2 pathway in the context of autoimmune disorders. We discuss the clinical potential of this signaling pathway in predicting disease activity and severity and offer possible future therapeutic alternatives. Graphical abstract

An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis Publication date: Available online 2 April 2019 Source: Cytokine & Growth Factor Reviews Author(s): Sabateeshan Mathavarajah, Jayme Salsman, Graham Dellaire Abstract Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis. Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms. One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE). In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.

The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Praveen Kumar L., Sangeetha Kandoi, Ranjita Misra, Vijayalakshmi S., Rajagopal K., Rama Shanker Verma Abstract Mesenchymal Stem Cells (MSCs) have been shown to be a promising candidate for cell-based therapy. The therapeutic potential of MSCs, towards tissue repair and wound healing is essentially based on their paracrine effects. Numerous pre-clinical and clinical studies of MSCs have yielded encouraging results. Further, these cells have been shown to be relatively safe for clinical applications. MSCs harvested from numerous anatomical locations including the bone marrow, adipose tissue, Wharton's jelly of the umbilical cord etc., display similar immunophenotypic profiles. However, there is a large body of evidence showing that MSCs secrete a variety of biologically active molecules such as growth factors, chemokines, and cytokines. Despite the similarity in their immunophenotype, the secretome of MSCs appears to vary significantly, depending on the age of the host and niches where the cells reside. Thus, by implication, proteomics-based profiling suggests that the therapeutic potential of the different MSC populations must also be different. Analysis of the secretome points to its influence on varied biological processes such as angiogenesis, neurogenesis, tissue repair, immunomodulation, wound healing, anti-fibrotic and anti-tumour for tissue maintenance and regeneration. Though MSC based therapy has been shown to be relatively safe, from a clinical standpoint, the use of cell-free infusions can altogether circumvent the administration of viable cells for therapy. Understanding the secretome of in vitro cultured MSC populations, by the analysis of the corresponding conditioned medium, will enable us to evaluate its utility as a new therapeutic option. This review will focus on the accumulating evidence that points to the therapeutic potential of the conditioned medium, both from pre-clinical and clinical studies. Finally, this review will emphasize the importance of profiling the conditioned medium for assessing its potential for cell-free therapy therapy.

Insulin-like growth factor binding proteins and angiogenesis: from cancer to cardiovascular disease Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Thomas Slater, Natalie J Haywood, Connor Matthews, Harneet Cheema, Stephen B Wheatcroft Abstract Angiogenesis is a tightly regulated activity that is vital during embryonic development and for normal physiological repair processes and reproduction in healthy adults. Pathological angiogenesis is a driving force behind a variety of diseases including cancer and retinopathies, and inhibition of angiogenesis is a therapeutic option that has been the subject of much research, with several inhibitory agents now available for medical therapy. Conversely, therapeutic angiogenesis has been mooted as having significant potential in the treatment of ischemic conditions such as angina pectoris and peripheral arterial disease, but so far there has been less translation from lab to bedside. The insulin-like growth factor binding proteins (IGFBP) are a family of seven proteins essential for the binding and transport of the insulin-like growth factors (IGF). It is being increasingly recognised that IGFBPs have a significant role beyond simply modulating IGF activity, with evidence of both IGF dependent and independent actions through a variety of mechanisms. Moreover, the action of the IGFBPs can be stimulatory or inhibitory depending on the cell type and environment. Specifically the IGFBPs have been heavily implicated in angiogenesis, both pathological and physiological, and they have significant promise as targeted cell therapy agents for both pathological angiogenesis inhibition and therapeutic angiogenesis following ischemic injury. In this short review we will explore the current understanding of the individual impact of each IGFBP on angiogenesis, and the pathways through which these effects occur.

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Gunnhildur Ásta Traustadóttir, Lene Vig Lagoni, Lea Bo Sønderlund Ankerstjerne, Hanne Cathrine Bisgaard, Charlotte Harken Jensen, Ditte Caroline Andersen Abstract Delta like non-canonical Notch ligand 1 (Dlk1) is an imprinted gene, mainly known for its involvement in adipogenesis, although it has been associated with many other stem cells/progenitors and is known to be widely expressed during organism development and tissue regeneration. In a systematic manner, we have outlined the overall expression pattern of Dlk1 in both man and mouse, and found Dlk1 to be expressed in tissues from all three germ layers. Yet, Dlk1 expression decreases along with increased differentiation as gestation proceeds and in most tissues Dlk1 is absent around birth. Thus, in adults, expression of Dlk1 is restricted to a few tissues and progenitor cells, but is re-expressed during disease and regeneration. Although diffferences exist, we found an overall conservation of Dlk1 expression between mouse and man, and conclude in that sense that the mouse is an appropiate model to study Dlk1. In agreement with the observed Dlk1 expression pattern, we found that the majority of published Dlk1 studies, report Dlk1 to have an inhibitory effect on both cell proliferation and differentiation, but the levels of the different DLK1 isoforms may be critical and have an impact on the overall outcome. This may also be an issue during tissue regeneration where several studies have reported Dlk1′s impact during skeletal muscle and liver regeneration without establishing the exact role. Likewise, the underlying mechanism of Dlk1 action is unknown, and seems to depend on both Notch dependent and independent pathways. However, from our data it is intriguing to speculate that the actual role of DLK1 may be to function as a checkpoint to slow down proliferation while forcing cells into the process of differentiation, and thus switch the cell/organ to a state of growth and hypertrophy. This may fit well with its reported impact on growth restiction and body size. Thus, our study which for the first time summarizes reported knowledge on Dlk1 in tissue development and regeneration as well as on the Dlk1 mechanism may provide novel insight to the general role of this remarkable imprinted gene in controlling cell growth, from which new hypotheses can be made in the field of stem cell biology and regenerative medicine. Graphical abstract

The regulation of circadian clock by tumor necrosis factor alpha Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Mustafa Gokhan Ertosun, Gamze Kocak, Osman Nidai Ozes Abstract All organisms display circadian rhythms which are under the control of the circadian clock located in the hypothalamus at the suprachiasmatic nucleus, (SCN). The circadian rhythms allow individuals to adjust their physiological activities and daily behavior for the diurnal changes in the living environment. To achieve these, all metabolic processes are aligned with the sleep/wake and fasting/feeding cycles. Subtle changes of daily behavior or food intake can result in misalignment of circadian rhythms. This can cause development of variety of metabolic diseases and even cancer. Although light plays a pivotal role for the activation of the master clock in SCN, the peripheral secondary clocks (or non-SCN), such as melatonin, growth hormone (GH), insulin, adiponectin and Ghrelin also are important in maintaining the circadian rhythms in the brain and peripheral organs. In recent years, growing body of evidence strongly suggest that CA2+ signaling, tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) also play very important roles in the regulation of circadian rhythms by regulating the transcription of the clock genes. Graphical abstract

Elabela and Apelin actions in healthy and pathological pregnancies Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Delphine Eberlé, Lucie Marousez, Sandy Hanssens, Claude Knauf, Christophe Breton, Philippe Deruelle, Jean Lesage Abstract Pregnancy is a dynamic and precisely organized process during which one or more baby develops. Embryonic development relies on the formation of the placenta, allowing nutrient and oxygen exchange between the mother and the fetus. Dysfunction of placental formation lead to pregnancy disorders such as preeclampsia (PE) with serious deleterious consequences for fetal and maternal health. Identifying factors involved in fetoplacental homeostasis could inform better diagnostic and therapeutic strategies for these pathological pregnancies. Here, we summarize actions of elabela, apelin and their common receptor APJ in the fetoplacental unit. Studies indicate that elabela is crucial for embryo cardiovascular system formation and early placental development, while apelin acts in mid/late gestation to modulate fetal angiogenesis and energy homeostasis. Most of these findings, drawn from animal models, indicate a key role of elabela/apelin-APJ system in the fetoplacental unit. This review also provides an overview of clinical studies investigating elabela/apelin-APJ system in pathological complicated pregnancies such as PE and gestational diabetes mellitus (GDM). While elabela-deficient mice display all the features of PE, current clinical studies show no difference in circulating elabela levels between PE and control patients which does not support a role in PE development. Conversely, apelin levels are increased during PE, but the use of apelin as an early PE marker remains to be fully investigated.

Editorial Board Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s):

Exploitation of phage display for the development of anti-cancer agents targeting fibroblast growth factor signaling pathways: New strategies to tackle an old challenge Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Behzad Jafari, Maryam Hamzeh-Mivehroud, Michael B. Morris, Siavoush Dastmalchi Abstract A tumor is defined as a group of cancer cells and 'surrounding' stromal bio-entities. Alongside the extracellular matrix (ECM) in the tumor microenvironment (TME), the stromal cells play key roles in cancer affliction and progression. Carcinoma-associated fibroblasts (CAFs) in the area of the tumor, whether activated or not, dictate the future of tumor cells. The CAFs and corresponding secreted growth factors (GFs), which mediate the crosstalk within the TME, can be targeted in therapies directed at the stroma. The impact of the fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling pathway in different kinds of tumors has been explored. Several tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and ligand traps targeting the formation of FGF-FGFR complex are in preclinical or early development phases. Moreover, there are numerous studies in the literature reporting the application of phage display technology for the development of peptides and proteins capable of functioning as FGF mimetics or traps, which are able to modulate FGF-related signaling pathways. In this review, prominent research in relation to phage display-assisted ligand identification for the FGF/FGFR system is discussed. Graphical abstract

Corrigendum to "New vaccination strategies in liver cancer" [Cytokine Growth Factor Rev. 36 (2017) 125–129] Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Luigi Buonaguro, Andrea Mayer-Mokler, Christian Flohr, Carsten Reinhardt, Harpreet Singh-Jasuja, Roberto Accolla, Giovanna Tosi, Yuk T. Ma, David Adams, Danila Valmori, Regina Heidenreich, Ulrike Gnad-Vogt, Alfred Königsrainer, Markus Löffler, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Maria Tagliamonte, Annacarmen Petrizzo, Maria Lina Tornesello