Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in-vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection.
Interleukin-27; HIV; cytokines; SPTBN1; therapy
Pre-B cell colony enhancing factor (PBEF) is regarded as a proinflammatory cytokine. Named for its first discovered function as a pre-B cell colony enhancing factor, it has since been found to have many other functions relating to cell metabolism, inflammation, and immune modulation. It has also been found to have intracellular and extracellular forms, with the two overlapping in function. Most of the intracellular functions of PBEF are due to its role as a nicotinamide phosphoribosyltransferase (Nampt). It has been found in human endothelial cells, where it is able to induce angiogenesis through upregulation of VEGF and VEGFR and secretion of MCP-1. In human umbilical endothelial cells, PBEF increases levels of the protease MMP 2/9. PBEF has also been found in a variety of immune cells other than B cells and has been shown to inhibit apoptosis of macrophages. Extracellular PBEF has been shown to increase inflammatory cytokines, such as TNF-α, IL-1β, IL-16, and TGF-β1, and the chemokine receptor CCR3. PBEF also increases the production of IL-6, TNF-α, and IL-1β in CD14+ monocyctes, macrophages, and dendritic cells, enhances the effectiveness of T cells, and is vital to the development of both B and T lymphocytes. The purpose of this review is to summarize the recent advances in PBEF research.
pre-B cell enhancing factor; cytokine; chemikine; monocyte; B lymphocyte; T lymphocyte
Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12–CXCR4 axis have emerged as additional or alternative agents for neoadjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of “selective blockade” of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.
CXC chemokines; Tumor growth; Angiogenesis; Metastasis
TGFβ is secreted in a latent state and must be
“activated” by molecules that facilitate its release from a
latent complex and allow binding to high affinity cell surface receptors.
Numerous molecules have been implicated as potential mediators of this
activation process, but only a limited number of these activators have been
demonstrated to play a role in TGFβ mobilization in
vivo. Here we review the process of TGFβ secretion and
activation using evolutionary data, sequence conservation and structural
information to examine the molecular mechanisms by which TGFβ is
secreted, sequestered and released. This allows the separation of more ancient
TGFβ activators from those factors that emerged more recently, and helps
to define a potential hierarchy of activation mechanisms.
TGFbeta; activation; evolution; LTBP; Extracellular matrix
The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.
CBM complex; Lymphoma; NF-κB; Targeted therapy
Latently infected resting CD4+ T cells are the major barrier to curing HIV. We have recently demonstrated that chemokines, which bind to the chemokine receptors CCR7, CXCR3 and CCR6, facilitate efficient HIV nuclear localisation and integration in resting CD4+ T cells, leading to latency. As latently infected cells are enriched in lymphoid tissues, where chemokines are highly concentrated, this may provide a mechanism for the generation of latently infected cells in vivo. Here we review the role of chemokines in HIV persistence; the main signalling pathways that are involved; and how these pathways may be exploited to develop novel strategies to reduce or eliminate latently infected cells.
Human immunodeficiency virus (HIV); Chemokine; Signalling; Latency; Persistence
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.
The discovery of the Suppressor Of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research.
SOCS; SOCS box; cytokine; receptor; JAK
Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren’s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
IL-22; Th17; Th22; autoimmune; therapeutic
The Snail/Gfi-1 (SNAG) family of zinc finger proteins is a group of transcriptional repressors that have been intensively studied in mammals. SNAG family members are similarly structured with an N-terminal SNAG repression domain and a C-terminal zinc finger DNA binding domain, however, the spectrum of target genes they regulate and the ranges of biological functions they govern vary widely between them. They play active roles in transcriptional regulation, formation of repressive chromatin structure, cellular signaling and developmental processes. They can also result in disease states due to deregulation. We have performed a thorough investigation of the relevant literature and present a comprehensive mini-review. Based on the available information, we also propose a mechanism by which SNAG family members may function.
SNAG repression domain; SNAG-ZFP target genes; Transcription Regulation; Cellular signaling and Development; EMT and Cancer
Mycobacterium tuberculosis (Mtb) is the intracellular pathogen that causes the disease, tuberculosis. Chemokines and chemokine receptors are key regulators in immune cell recruitment to sites of infection and inflammation. This review highlights our recent advances in understanding the role of chemokines and chemokine receptors in cellular recruitment of immune cells to the lung, role in granuloma formation and host defense against Mtb infection.
Tuberculosis; Chemokines; lung
Although the causes of inflammatory arthritis elude us, aberrant cytokine expression has been linked to joint pathology. Consequently, several approaches in the clinic and/or in clinical trials are targeting cytokines, e.g. tumor necrosis factor (TNF), interleukin 23 (IL-23) and interleukin 17 (IL-17), with the goal of antagonizing their respective biologic activity through therapeutic neutralizing antibodies. Such, cytokine signaling-dependent molecular networks orchestrate synovial inflammation on multiple levels including differentiation of myeloid cells to osteoclasts, the central cellular players in arthritis-associated pathologic bone resorption. Hence, understanding of the cellular and molecular mechanisms elicited by synovial cytokine networks that dictate recruitment, differentiation and activation of osteoclast precursors and osteoclasts, respectively, is central to shaping novel therapeutic options for inflammatory arthritis patients. In this article we are discussing the complex signaling interactions involved in the regulation of inflammatory arthritis and it’s associated bone loss with a focus on interleukin 27 (IL-27). The present review will discuss the primary bone-degrading cell, the osteoclast, and on how IL-27, directly or indirectly, modulates osteoclast activity in autoimmune-driven inflammatory joint diseases.
It is time for those working on oncolytic viruses to take stock of the status of the field. We now have at our disposal an array of potential therapeutic agents, and are beginning to conduct early-phase clinical trials in patients with relapsed/metastatic cancers. By drawing on lessons learned during the development of other biological therapies, such as monoclonal antibodies and targeted small molecule inhibitors, we are now in a position to chart the course of the next wave of trials that will go beyond the phase I studies of safety and feasibility. In this article we review our approach to the development of oncolytic viruses as cancer therapeutics. In doing so, we emphasise the fact that this process is modular and involves multiple iterative steps between the laboratory and the clinic. Ultimately, at least in the medium term, the future of oncolytic virotherapy lies in combination regimens with standard anti-cancer agents such as radiation and chemotherapy.
Oncolytic virus; Reovirus; Chemotherapy; Radiotherapy; Clinical trial
Connective tissue growth factor (CTGF/CCN2) is a cysteine-rich matricellular secreted protein that regulates diverse cell functions including adhesion, migration, proliferation, differentiation, survival, senescence and apoptosis. In the pancreas, CTGF/CCN2 regulates critical functions including β cell replication during embryogenesis, stimulation of fibrogenic pathways in pancreatic stellate cells during pancreatitis, and regulation of the epithelial and stromal components in pancreatic ductal adenocarcinoma. This article reviews the evidence establishing CTGF/CCN2 as an important player in pancreatic physiology and pathology, highlighting the specific cell types that are involved in each process and the importance of CTGF/CCN2 as a component of autocrine or paracrine signaling within or between these various cells. Translational applications, including the potential for CTGF/CCN2-based therapies in diabetes, fibrosis, or cancer are discussed.
Connective tissue growth factor; pancreatic stellate cell; islets; β cell; acinar cell; desmoplasia; fibrosis; pancreatic ductal adenocarcinoma; matricellular; CCN; CCN2; CTGF; TGF-β
Transforming growth factor betas (TGFβs) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFβ ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFβs appear to be involved in epithelial–mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial–mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFβs are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin–angiotensin system. The evidence for TGFβ activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.
TGFβ; Heart; Vasculature; Development; Physiology
Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as the defining hallmark of the disease. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including the identification of precursor lesions, sequential transformation from normal pancreas to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of those alterations on malignant behaviors. However, the current therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to have significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor’s mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and their stroma will be important to designing new, effective therapeutic strategies for pancreatic cancer. This review focuses on the origination of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration between these two components.
Cytokines; growth factors; transcriptional factors; therapy; immunology
HIV persists in cellular and anatomical reservoirs during Highly Active Antiretroviral Therapy (HAART). In vitro studies as well as in vivo observations have identified cytokines as important factors regulating the immunological and virological mechanisms involved in HIV persistence. Immunosuppressive cytokines might contribute to the establishment of viral latency by dampening T cell activation and HIV production, thereby creating the necessary immuno-virological condition for the establishment of a pool of latently infected cells. Other cytokines that are involved in the maintenance of memory CD4+ T cells promote the persistence of these cells during HAART. Conversely, proinflammatory cytokines may favor HIV persistence by exacerbating low levels of ongoing viral replication in lymphoid tissues even after prolonged therapy. The ability of several cytokines to interfere with the molecular mechanisms responsible for HIV latency makes them attractive candidates for therapeutic strategies aimed at reducing the pool of latently infected cells. In this article, we review the role of cytokines in HIV persistence during HAART and discuss their role as potential eradicating agents.
HIV; Viral reservoirs; Cytokines; Memory CD4+ T cells; HAART; IL-7; IL-2
Chronic HIV infection, which is primarily characterized by the progressive depletion of total CD4+ T cells, also causes persistent inflammation and immune activation. This is followed by profound changes in cellular and tissue microenvironments that often lead to prolonged immune dysfunction. The global nature of this immune dysfunction suggests that factors that are involved in immune cell survival, proliferation, differentiation and maturation are all affected. Of particular interest is the transcriptional factor Foxo3a that regulates a number of genes that are critical in the development and the maintenance of T and B cells, dendritic cells (DCs) and macrophages. Alterations in the microenvironment mediated by HIV infection cause significant increase in the transcriptional activity of Foxo3a; this has major impact on T cell and B cell immunity. In fact, recent findings from HIV infected individuals highlight three important points: 1) The alteration of Foxo3a signaling during HIV infection deregulates innate and adaptive immune responses; 2) Foxo3a-mediated effects are reversible and could be restored by interfering with the Foxo3a pathway; and 3) down-regulation of Foxo3a transcriptional activity in elite controllers (ECs) represents a molecular signature, or a correlate of immunity, associated with natural protection and lack of disease progression. In this review, we will discuss how HIV-infection altered microenvironments could result in impaired immune responses via the Foxo3a signaling pathway. Defining precisely the molecular mechanisms of how persistent inflammation and immune activation are able to influence the Foxo3a pathway could ultimately help in the development of novel approaches to improve immune responses in HIV infected subjects.
Foxo3a; HIV; microenvironment; EC; apoptosis; memory
From early in the HIV epidemic it was appreciated that many inflammatory markers such as neopterin and TNF-α were elevated in patients with AIDS. With the advent of modern technology able to measure a broad array of cytokines, we now know that from the earliest points of infection HIV induces a cytokine storm. This review will focus on how cytokines are disturbed in HIV infection and will explore potential therapeutic uses of cytokines. These factors can be used directly as therapy during HIV infection, either to suppress viral replication or prevent deleterious immune effects of infection, such as CD4+ T cell depletion. Cytokines also show great promise as adjuvants in the development of HIV vaccines, which would be critical for the eventual control of the epidemic.
HIV; cytokine; chemokine; immune activation; vaccine
Interleukin (IL)-21 is one of a group of cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15 whose receptor complexes share the common γ chain (γc). Secretion of IL-21 is restricted mainly to T follicular helper (TFH) CD4 T cell subset with contributions from Th17, Natural Killer (NK) T cells, but the effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. The role of IL-21 in sustaining and regulating T cell, B cell and NK cell responses during chronic viral infections has recently come into focus. This chapter reviews current knowledge about the biology of IL-21 in the context of HIV infection.
IL-21 and T cells; IL-21 and B cells; HIV and IL-21; immunomodulation by IL-21; IL-21 and immunity
Numerous studies have characterized the cytokine modulation observed in human immunodeficiency virus (HIV) infected individuals, from initial infection through chronic disease. Progressive and non-progressive HIV infection models show the cytokine milieu differs in terms of production and responsiveness in these two groups, suggesting an understanding of the role cytokines play during infection is necessary for directing the immune response toward viral control. This review will cover cytokine induction and dysfunction during HIV pathogenesis, with a focus on the interplay between cytokines and transcription factors, T cell activation, and exhaustion. We highlight cytokines that have either vaccine adjuvant or therapeutic potential and discuss the need to identify key factors required for prevention of progression, clearance of infection, or protection from acquisition.
HIV; T cells; Transcription factors; Cytokines; Vaccines
HIV immune activation plays an important role in the immunopathogenesis of the disease. The mechanisms driving this immune activation are partially defined and likely are the result of multiple factors. The introduction of combination antiretroviral therapy (cART) has improved the life expectancy of HIV infected individuals, however there is evidence that in the setting of “undetectable” HIV-RNA plasma levels, there is some level of persistent immune activation in these patients. A better understanding of the immune activation pathways should be of value in developing complementary therapies to restore the immune systems’ of patients with HIV infection. This review discuss the cytokine mediated pathways of immune activation of the CD4 and CD8 T cell pools during HIV infection.
CD4 and CD8 T cell immune activation; T cell homeostasis; IL-7; Type-I IFN
The BMP signaling pathway controls a number of cell processes during development and in adult tissues. At the cellular level, ligands of the BMP family act by binding a hetero-tetrameric signaling complex, composed of two type I and two type II receptors. BMP ligands make use of a limited number of receptors, which in turn activate a common signal transduction cascade at the intracellular level. A complex regulatory network is required in order to activate the signaling cascade at proper times and locations, and to generate specific downstream effects in the appropriate cellular context.
One such regulatory mechanism is the repulsive guidance molecule (RGM) family of BMP co-receptors. This article reviews the current knowledge regarding the structure, regulation, and function of RGMs, focusing on known and potential roles of RGMs in physiology and pathophysiology.
BMP; receptors; RGM; DRAGON; HJV
A vast number of cellular processes and signaling pathways are regulated by various receptors, ranging from transmembrane to nuclear receptors. These receptor-mediated processes are modulated by a diverse set of regulatory proteins. TNFα-induced protein 3-interacting protein 1 is such a protein that inhibits both transduction by transmembrane receptors, such as TNFα-receptor, EGF-R, and TLR, and nuclear receptors’ PPAR and RAR activity. These receptors play key roles in regulating inflammation and inflammatory diseases. A growing number of references have implicated TNIP1 through GWAS and expression studies in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, although TNIP1’s exact role has yet been determined. In this review, we aim to integrate the current knowledge of TNIP1’s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases.
TNIP1; ABIN-1; TNFα receptor; nuclear receptor; inflammation