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Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Diabetes is a growing public health problem. Diabetic kidney disease (DKD) is the most prevalent chronic renal disease and the major cause of end-stage renal failure worldwide, predominantly due to the increase of Type 2 diabetes associated with obesity. The intimate mechanisms leading to the development and progression of renal injury in DKD are not well understood, but current knowledge indicates that its pathogenesis is multifactorial, where the immune response and inflammation appear to be relevant factors., Summary: This review summarizes the role of relevant inflammatory molecules and pathways that participate in the development of DKD. Likewise, we focused on the new therapeutic approaches based on anti-inflammatory effects of different drugs. Key Messages: This new pathogenic perspective of DKD as an inflammatory condition leads to novel horizons, such as the potential role of inflammatory signaling pathways and their downstream products as emerging biomarkers and promising therapeutic targets., (© 2018 S. Karger AG, Basel.)

The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrate that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with the addition of a chemokine binding domain as soluble decoy receptors.

Platelets are well recognized as a key cell component of the hemostatic system. Recently, several additional functions have been discovered for these blood cells but most importantly in the process of inflammation. Numerous research groups have demonstrated crucial roles for platelets in the pathogenesis of varied clinical conditions where inflammation is important. Alterations in both platelet number and function have been observed with these different conditions. The relevance of these findings is their therapeutic implications through simple antiplatelet therapy to more complex, as yet clinically untrialed options, like interfering with platelet-leukocyte or platelet-endothelial interaction. This review focuses on how platelets are relevant in inflammatory conditions with an impetus on the clinical aspects., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The diversity of integrins and their complex role in many diseases suggests great potential for this superfamily as drug targets. The initial successes of anti-integrin therapeutics in the treatment of thrombotic disorders suggested that similar anti-integrin agents could be developed for the treatment of inflammatory disorders. While initially a promising strategy, inhibition of the integrins proved to be elusive despite the discovery of highly potent inhibitors. This is due to several reasons, including redundancy among the integrins and the importance of integrins in key physiological systems. Further exploration of the selective role for distinct leukocytic integrins indicated that homing of inflammatory cells to select disease sites depends on a highly regulated expression of discrete integrins and their ligands in limited locations. Selective control of integrin function is also regulated by local chemokines permitting exquisite homing of populations of inflammatory cells to disease sites. A more complete understanding of the regulation of integrin activation in disease states will permit the development of more effective and specific anti-integrin therapeutic agents., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury.

Deregulated inflammatory response plays a pivotal role in the initiation, development and progression of tumours. Potential molecular mechanism(s) that drive the establishment of an inflammatory-tumour microenvironment is not entirely understood owing to the complex cross-talk between pro-inflammatory and tumorigenic mediators such as cytokines, chemokines, oncogenes, enzymes, transcription factors and immune cells. These molecular mediators are critical linchpins between inflammation and cancer, and their activation and/or deactivation are influenced by both extrinsic (i.e. environmental and lifestyle) and intrinsic (i.e. hereditary) factors. At present, the research pertaining to inflammation-associated cancers is accumulating at an exponential rate. Interest stems from hope that new therapeutic strategies against molecular mediators can be identified to assist in cancer treatment and patient management. The present review outlines the various molecular and cellular inflammatory mediators responsible for tumour initiation, progression and development, and discusses the critical role of chronic inflammation in tumorigenesis.

Chemerin is a pro-inflammatory adipokine secreted and expressed predominantly by adipocytes. Chemerin is initially involved in the regulation of the immune system, the adipogenesis and the energy metabolism. However, several recent studies show that this adipokine and its receptors are present in the gonads. In vitro, chemerin reduces steroidogenesis in ovarian and testicular cells in rodents and humans. Chemerin and its receptors are also present in the placenta. Chemerin plays an important role in the regulation of fetal and maternal metabolism, fetal growth and metabolic homeostasis during pregnancy. This review describes the role of chemerin in metabolism and reproduction., (© 2015 médecine/sciences – Inserm.)

Introduction: Prostate cancer is the most common non-cutaneous malignancy diagnosed in men. Moving from histological observations since a long time, it has been recognized that innate and adaptive immunity actively participates in the pathogenesis, surveillance, and progression of prostate cancer., Materials and Methods: A PubMed and Web of Science databases search was performed for studies providing evidence on the roles of the innate and adaptive immunity during the development and progression of prostate cancer., Conclusions: There are growing evidences that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumor microenvironment. This review discusses the role played by the innate and adaptive immune system in the local progression of prostate cancer, and the prognostic information that we can currently understand and exploit.

This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries., (© 2014 American Heart Association, Inc.)

Osteoarthritis (OA) is a whole joint disease, in which thinning and disappearance of cartilage is a critical determinant in OA progression. The rupture of cartilage homeostasis whatever its cause (aging, genetic predisposition, trauma or metabolic disorder) induces profound phenotypic modifications of chondrocytes, which then promote the synthesis of a subset of factors that induce cartilage damage and target other joint tissues. Interestingly, among these factors are numerous components of the inflammatory pathways. Chondrocytes produce cytokines, chemokines, alarmins, prostanoids, and adipokines and express numerous cell surface receptors for cytokines and chemokines, as well as Toll-like receptors. These receptors activate intracellular signaling pathways involved in inflammatory and stress responses of chondrocytes in OA joints. This review focuses on mechanisms responsible for the maintenance of cartilage homeostasis and highlights the role of inflammatory processes in OA progression.

Chemerin is an adipocyte-secreted protein with autocrine/paracrine roles on adipose development and function as well as endocrine roles in metabolism and immunity. Following prochemerin secretion, protease-mediated generation of chemerin isoforms with a range of biological activities is a key regulatory mechanism controlling local, context-specific chemerin bioactivity. Together, experimental and clinical data indicate that localized and/or circulating chemerin expression and activation are elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. These elevations are positively correlated with deleterious changes in glucose, lipid, and cytokine homeostasis, and may serve as a link between obesity, inflammation and other metabolic disorders. This review highlights the current state of knowledge regarding chemerin expression, processing, biological function and relevance to human disease, particularly with respect to adipose tissue development, inflammation, glucose homeostasis and cardiovascular disease. Furthermore, it discusses study variability, deficiencies in current measurement, and questions concerning chemerin function in disease, with a special emphasis on techniques and tools used to properly assess chemerin biology. An integration of basic and clinical research is key to understanding how chemerin influences disease pathobiology, and whether modulation of chemerin levels and/or activity may serve as a potential method to prevent and treat metabolic diseases., (© 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity.)

Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Chemerin is a recently identified adipocytokine which plays a role on inflammation and adipocytes metabolism. However, its function in vasculature is largely unknown. We examined the effects of chemerin on vascular endothelial inflammatory states. Treatment of human umbilical vein endothelial cells with chemerin (300 ng/ml, 20 min) induced phosphorylation of Akt (Ser473) and endothelial nitric oxide (NO) synthase (eNOS) (Ser1177). Consistently, chemerin increased intracellular cyclic GMP content. Pretreatment with chemerin (1-300 ng/ml, 24 h) significantly inhibited phosphorylation of nuclear factor (NF)-κB p65 (Ser536) and p38 as well as vascular cell adhesion molecule (VCAM)-1 expression induced by tumor necrosis factor (TNF)-α (5 ng/ml, 20 min-6 h). Inhibitor of NF-κB or p38 significantly inhibited the TNF-α-induced VCAM-1 expression. Chemerin also inhibited TNF-α-induced VCAM-1 expression in rat isolated aorta. Moreover, chemerin significantly inhibited monocytes adhesion to TNF-α-stimulated endothelial cells. The inhibitory effect of chemerin on TNF-α-induced VCAM-1 was reversed by a NOS inhibitor. Conversely, an NO donor, sodium nitroprusside significantly inhibited TNF-α-induced VCAM-1. The present results for the first time demonstrate that chemerin plays anti-inflammatory roles by preventing TNF-α-induced VCAM-1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-κB and p38 through stimulation of Akt/eNOS signaling and NO production., (Copyright © 2012 Elsevier Inc. All rights reserved.)

There is growing evidence for the importance of chronic inflammation in the pathogenesis of adult cancers and for an ongoing role of the inflammatory response in tumor growth and metastasis. Here, we examine how these processes relate to pediatric malignancies. While it is unlikely that chronic inflammation plays a significant role in driving malignant progression in childhood tumors that typically have developmental origins, the inflammatory response does appear to play an important role in the development and progression of many types of childhood cancer. An enhanced understanding of these processes will be of critical importance in developing novel therapeutic strategies., (Copyright © 2011 Wiley Periodicals, Inc.)

The basic elements of wound healing can be described using three sequential and overlapping phases: inflammation, proliferation and regeneration. These phases represent a highly organized, tightly regulated and complex sequence of events that are dependent on an exquisite balance between various cell types and mediators. Inflammation is a prerequisite to healing; however, chronic wounds in particular exhibit a prolonged inflammatory response, thus providing an ideal environment for bacterial infiltration and proliferation. Considering that approximately 70% of all wounds are chronic, with the majority of wound care being delivered in the community, this paper aims to support nurses in their understanding of inflammation in order to enhance clinical practice.

Defined by the presence of endometrial-like cells outside the uterus, endometriosis is one of the most diagnosed gynecological disorders, affecting 5 to 10 % of reproductive age women, but the true incidence is unknown. Endometriosis is a major cause of pelvic pain, dysmenorrhea, dyspareunia, infertility and menstrual irregularities, but there is no clear correlation between the symptoms and the extent of the disease. Despite decades of intensive investigations, little is known about the pathogenesis of endometriosis. The disease is often associated with chronic pelvic inflammation. Abnormal levels of immune cells such macrophages, dendritic and natural killer cells were found in the peritoneal cavity of patients. However these cells seem to be unable to detect and eliminate ectopic endometrial cells. Several studies showed that peritoneal immune cells are dysfunctional and may rather contribute to endometriosis development. A review of relevant clinical and scientific studies was carried out. This review sheds light on cellular and immunological pro-inflammatory changes which were observed in patients with endometriosis, their impact on angiogenesis, apoptosis, extracellular matrix remodeling and hormonal production and consequences on fertility.

Chemoattractants are pivotal mediators of host defense, orchestrating the recruitment of immune cells into sites of infection and inflammation. Chemoattractants display vast chemical diversity and include bioactive lipids, proteolytic fragments of serum proteins, and chemokines (chemotactic cytokines). All chemoattractants induce chemotaxis by activating seven-transmembrane-spanning GPCRs expressed on immune cells, establishing the concept that all chemoattractants are related in function. However, although chemoattractants have overlapping functions in vitro, recent in vivo data have revealed that they function, in many cases, nonredundantly in vivo. The chemically diverse nature of chemoattractants contributes to the fine control of leukocyte trafficking in vivo, with sequential chemoattractant use guiding immune cell recruitment into inflammatory sites. Lipid mediators frequently function as initiators of leukocyte recruitment, attracting the first immune cells into tissues. These initial responding immune cells produce cytokines locally, which in turn, induce the local release of chemokines. Local chemokine production then markedly amplifies subsequent waves of leukocyte recruitment. These new discoveries establish a paradigm for leukocyte recruitment in inflammation--described as lipid-cytokine-chemokine cascades--as a driving force in the effector phase of immune responses.

Hypertension, especially for elevated renin-angiotensin II (Ang II), induces cardiac fibrosis and remodeling. Ang II, acting via its receptors, causes both hemodynamic and nonhemodynamic effects. These effects trigger a series of inflammatory responses. Recent studies have demonstrated that hypertension stimulates infiltration of leukocytes into heart, and interaction among macrophages, T cells, and monocytic fibroblast precursor cells regulates the imbalance of pro-inflammatory and anti-inflammatory factors. Several studies have demonstrated that the inflammatory microenvironment in hypertensive heart promotes a forward feedback infiltration of leukocytes, differentiation of monocytes, and formation of myofibroblasts. An increased number of myofibroblasts, the dominant source of extracellular matrix production, results in deposition of collagen and cardiac remodeling. A thorough understanding of the pathological process underlying hypertension-induced cardiac remodeling may help in prevention and treatment.

Despite considerable progress over the last decades, acute myocardial infarction continues to remain the major cause of morbidity and mortality worldwide. The present therapies include only cause-dependent interventions, which are not able to reduce myocardial necrosis and optimize cardiac repair following infarction. This review highlights the cellular and molecular processes after myocardial injury and focuses on chemokines, the main modulators of the inflammatory and reparatory events, as the most valuable drug targets., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In adults, mesenchymal stromal cells contain tissue-specific multipotent stem cells, MSC, which can be found throughout the body. With advancing age, tight controls of regulatory networks, which guide MSC biology, gradually deteriorate. Aberrations within the MSC microenvironment such as chronic inflammation eventually lead to adverse manifestations, such as the accumulation of fat deposits in bone and muscles, impaired healing and fibrosis after severe injury, or altered hematopoiesis and autoimmunity. MSC can also specifically interact with a large variety of immune cells, and in doing so, they secrete cytoprotective and immunoregulatory molecules, which together with intercellular contacts mediate immune modulatory processes. This review comprehends the current knowledge regarding molecular mechanisms and cellular interactions that occur in stem cell niches, which are jointly shared between MSC and hematopoietic stem and progenitor cells, as well as those intracellular interdependences taking place between mesenchymal and a wide variety of hematopoietic progeny in particular T lymphocytes, which eventually perturb tissue homeostasis and immunology at advanced age., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mast cells (MCs) are motile granule-containing cells that originate from bone marrow pluripotential haematopoietic cells, circulate in blood and extravasate in tissues where they play an important role in inflammation, host defense and tissue repair. We herein review the English literature over the past twenty years concerning the biology and function of MCs with particular focus on their role in the inflammatory process in dental implant failure due to osseointegration absence or to peri-implantitis. Due to immunological or non-immunological stimulation, in a few minutes MCs release prestored granule-associated mediators into the extracellular environment promoting pro-/anti-inflammatory events/response. MCs can either protect the host by activating defense mechanisms and initiating tissue repair and osseointegration if their function is transient, or lead to considerable tissue damage if it is inappropriate and continuous leading to osseointegration absence or peri-implantitis. We hypothesize that administration of histamine receptor antagonists, serine protease inhibitors and MC preformed mediator release inhibitors before and after implantation could represent novel therapeutic strategies to improve the osseointegration, the functionality and longevity of implants or prevent and treat peri-implant inflammatory conditions.

Necrotic cells release dozens, possibly hundreds, of molecules that stimulate the inflammatory response. Healthy cells in the environment react to these by secreting other inflammatory mediators to amplify the response. In response to acute necrotic injury in the liver, neutrophils follow a restricted set of molecular cues to move along the sinusoids through the inflamed tissue and into the zone of necrosis, as demonstrated by intravital microscopy to view leukocyte migration live and in real time. Necrosis initiates an intricate interplay between damage-associated molecular pattern molecules, stromal inflammatory cells, and neutrophils. This results in a series of clear molecular signals, enabling neutrophils to follow an intravascular chemokine gradient along the sinusoid in the region where blood still circulates and a formyl peptide gradient through the nonperfused region to the necrotic focus.

Atherosclerosis is recognized as an inflammatory condition of the vessel wall, characterized by accumulation of inflammatory cells such as macrophages and T cells. There are accumulating evidences that chemokines, cytokines, and lipid mediators coordinately modulate platelet- or leukocyte-endothelial cell interactions, and contribute to the maintenance of vascular homeostasis. This review focuses on the role of lipid mediators, especially those derived from polyunsaturated fatty acids, in controlling vascular inflammation and the progression of atherosclerosis.

Inflammation is one of the first immune system responses to any type of aggression. As with any type of aggression, the lesion produced by inhalation of tobacco smoke prompts an innate inflammatory response. Subsequently, this lesion is stimulated by the release of various chemical factors that enhance the inflammatory response and, finally--depending on the type of aggression--acquired immunity is activated, which, mediated by lymphocyte participation, serves to establish a physical barrier against the propagation of the lesion and to aid repair of the damaged pulmonary tissue. However, the balance between inflammation and repair is not always maintained, as is the case in chronic obstructive pulmonary disease (COPD), in which marked changes appear in the architecture of the airways, alveolar spaces and pulmonary arteries, forming the structural background of the functional changes characteristic of this disease. COPD is basically a pulmonary disease but data are available on the existence of associated systemic inflammation. The origins of this systemic inflammation are unclear: some information indicates that tobacco smoke is a direct origin common to local and systemic inflammation, while other data point to primary pulmonary inflammation that secondarily produces systemic involvement. The present review describes the main mechanisms involved in both pulmonary and systemic inflammation in COPD., (Copyright © 2010 Sociedad Española de Neumología y Cirugía Torácica. Published by Elsevier Espana. All rights reserved.)

Chemerin is a secreted protein with a complex but well-established role in immune function. Parallel lines of investigation also support the notion that chemerin is a novel adipokine that regulates adipocyte development and metabolic function as well as glucose metabolism in liver and skeletal muscle tissues. A growing body of human experimental data indicates that serum chemerin levels are elevated in patients with obesity and that they exhibit a positive correlation with various aspects of the metabolic syndrome. Thus, the dual role of chemerin in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Observational studies have suggested that lifestyle risk factors such as tobacco, alcohol, high-fat diet, radiation, and infections can cause cancer and that a diet consisting of fruits and vegetables can prevent cancer. Evidence from our laboratory and others suggests that agents either causing or preventing cancer are linked through the regulation of inflammatory pathways. Genes regulated by the transcription factor NF- kappaB have been shown to mediate inflammation, cellular transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Whereas various lifestyle risk factors have been found to activate NF- kappaB and NF- kappaB-regulated gene products, flavonoids derived from fruits and vegetables have been found to suppress this pathway. The present review describes various flavones, flavanones, flavonols, isoflavones, anthocyanins, and chalcones derived from fruits, vegetables, legumes, spices, and nuts that can suppress the proinflammatory cell signaling pathways and thus can prevent and even treat the cancer., (Georg Thieme Verlag KG Stuttgart-New York.)

Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumours that are not epidemiologically related to inflammation. Compounds of the inflammatory tumor microenvironment include leukocytes, cytokines, complement components, and are orchestrated by transcription factors, such as NFkB and Stat3. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. An intrinsic (driven by genetic events that cause neoplasia) and an extrinsic (driven by inflammatory conditions which predispose to cancer) pathway link inflammation and cancer. Smouldering inflammation in the tumour microenvironment promotes proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, response to hormones and chemotherapeutic agents. Cancer-related inflammation represents a target for innovative diagnostic and therapeutic strategies.

Heparan sulfate proteoglycans (HSPGs) are glycoconjugates that are implicated in various biological processes including development, inflammation and repair, which is based on their capacity to bind and present several proteins via their carbohydrate side chains (glycosaminoglycans; GAGs). Well-known HSPGs include the family of syndecans and glypicans, which are expressed on the plasma membrane and perlecan, agrin and collagen type XVIII, which are present in basement membranes. In this review, we provide an overview of the current knowledge on the role and regulation of HSPGs in leukocyte extravasation. In the non-inflamed endothelial glycocalyx HSPGs are anti-adhesive, and there are several indications that active regulation of HSPG core protein expression and/or GAG modification occurs upon inflammation. We address the current evidence for the role of HSPGs in leukocyte extravasation through interaction with the leukocyte adhesion molecule L-selectin, chemokines and other binding partners. Finally, a number of possibilities to use HSPGs as therapeutics or targets in anti-inflammatory strategies are discussed.

Angiogenesis and inflammation are closely integrated processes in a number of physiological and pathological conditions, including wound healing, psoriasis, diabetic retinopathy, rheumatoid arthritis, arteriosclerosis, and cancer. Fibroblast growth factor-2 (FGF2) belongs to the family of the heparin-binding FGF growth factors. FGF2 exerts its pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Elevated levels of FGF2 have been implicated in the pathogenesis of several diseases characterized by a deregulated angiogenic/inflammatory response. FGF2 induces the expression of a wide repertoire of inflammation-related genes in endothelial cells, including pro-inflammatory cytokines/chemokines and their receptors, endothelial cell adhesion molecules, and components of the prostaglandin pathway. Consistent with this pro-inflammatory signature, in vivo evidence points to a non-redundant role for chemokines and infiltrating monocytes/macrophages in FGF2-driven neovascularization. This review will focus on the cross-talk between FGF2 and the inflammatory response in the modulation of blood vessel growth.

Recent studies have challenged the conventional hypothesis that inflammation is the major player in the fibrosis cascade. Emerging evidence points to a critical role for interactions between tissue-resident and infiltrating, non-resident cells, in mediating fibrotic responses. Improved understanding of the biology of extracellular matrix (ECM) remodeling and the pathways that regulate assembly of the ECM and its interactions with growth factors/cytokines have led to the identification of new and attractive therapeutic targets. These include molecules that regulate fibrocytic cell infiltration, epithelial and myofibroblast differentiation, ECM synthesis and degradation. However, it is imperative that these new therapies be timed and compartmentalized to target the tissue of interest, as the dynamics of cellular differentiation and ECM remodeling may be different between organ systems. This review will summarize the current understanding of the mechanisms involved in the development of fibrosis, based on recent in vitro and in vivo studies, and comment on novel molecular pathways for drug discovery.

Inflammatory conditions in some tissues increase the risk of cancer. Cytokines and chemokines are components of an intensive dialog promoting angiogenesis, metastasis, subversion of adaptive immunity and changing response to hormones and to chemotherapeutic agents. Cytokines involved in cancer-related inflammation represent a target for innovative diagnostic and therapeutic strategies, and a future challenge for scientists and clinicians.

This article gives basic information about the formation and the course of the inflammatory reaction, which is the important adaptation mechanism of the organism on the various external and internal injurants. The main attention is fixated on the role of the immune system in the course of the inflammatory reaction. It deals with the presence and the sense of the inflammatory reaction in the tumour environment in more detail. It gives the short information about the mechanisms of the antitumour defence. The influence ofthe inflammatory reaction on the genesis, the course and the progression of the tumour disease is discussed in the third chapter.

Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis.

The link between inflammation and cancer proposed more than a century ago by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, has recently found a number of genetic and molecular confirmations. Experimental, clinical and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to different types of cancer. Cancer-associated inflammation includes: the presence of leukocyte infiltration; the expression of cytokines such as tumor necrosis factor (TNF) or interleukin (IL)-1; chemokines such as CCL2 and CXCL8; active tissue remodelling and neo-angiogenesis. Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Many observations indicate that, in the tumor micro-environment, TAM have several protumoral functions, including expression of growth factors, matrix proteases, promotion of angiogenesis and suppression of adaptive immunity. In this review we will discuss the role of TAM in the inflammatory micro-environment of solid tumors and will try to identify potential target for future therapeutic approaches.

Mice lacking matrix metalloproteinase-3 (MMP-3; stromelysin-1) demonstrated significantly less injury than their normal counterparts following the formation of IgG-containing immune complexes in the alveolar wall or in the wall of the peritoneum. Likewise, mice lacking MMP-3 demonstrated less lung injury following intra-tracheal instillation of the chemotactic cytokine macrophage inhibitory protein-2 (MIP-2) than did mice with MMP-3. There was a relationship between tissue injury (evidenced histologically) and accumulation of anti-laminin 111 immunoreactive material in the bronchoalveolar lavage (BAL) or peritoneal lavage (PL) fluid. There was also a relationship between tissue injury and influx of neutrophils into the BAL or PL fluid. Taken together, these data demonstrate an important role for MMP-3 in acute inflammatory tissue injury.

Inflammation is a fundamental process that protects organisms by removing or neutralizing injurious agents. A key event in the inflammatory response is the localized recruitment of various leukocyte subsets. Here we address the cellular and regulatory mechanisms of leukocyte recruitment to the vessel wall in cardiovascular disease and discuss our evolving understanding of the role of the vascular endothelium in this process. The vascular endothelium is the continuous single-cell lining of the cardiovascular system that forms a critical interface between the blood and its components on one side and the tissues and organs on the other. It is heterogeneous and has many synthetic and metabolic functions including secretion of platelet-derived growth factor, von Willebrand factor, prostacyclin, NO, endothelin-1, and chemokines and the expression of adhesion molecules. It also acts as a nonthrombogenic and selective permeable barrier. Endothelial cells also interact closely with the extracellular matrix and with adjacent cells including pericytes and smooth muscle cells within the vessel wall. A central question in vascular biology is the role of the endothelium in the initiation of inflammatory response, the extent of its "molecular conversations" with recruited leukocytes, and its influence on the extent and/or outcome of this response.

Inflammation is essential for protection from infection and for the repair of damaged tissue. Much is now known about how inflammation is induced and maintained, but the processes underlying the resolution of inflammation are often overlooked. However, resolution is an essential component of all successful inflammatory responses because it ensures the restoration of tissue homeostasis and prevents immunopathology of the type seen in chronic inflammatory diseases and autoimmunity. Small secreted proteins called chemokines, acting through chemokine receptors, are known to be critical regulators of leukocyte recruitment and function during the initiation and maintenance of inflammation. Thus, their efficient removal would seem to be a prerequisite for successful resolution. In recent years, it has emerged that specialized chemokine "decoy" receptors exist that actively participate in this process. Moreover, other chemokine receptors have been proposed to lead a double life and perform opposing roles during inflammation: leukocyte recruitment (by signaling) and resolution (by chemokine sequestration). A recent study provides further support for this theory by showing that apoptotic inflammatory leukocytes increase the number of surface chemokine receptors and that these receptors can remove chemokines from inflamed tissue. Leukocyte apoptosis is already known to aid resolution, not just because it eliminates leukocytes from inflamed tissues, but also because their consumption by macrophages leads to the production of anti-inflammatory cytokines. The new work indicates that chemokine sequestration may be another mechanism exploited by dying cells to assist in the resolution of inflammation.

Our view of white adipose tissue (WAT) has changed over the last decade, from an inert triglyceride storage tissue to a highly active metabolic organ. Indeed, WAT secretes proinflammatory cytokines such TNF-a, interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-6 (IL-6), and chemokines such as monocyte chemoattractant protein-1 (MCP-1), interferon gamma inducible protein 10 (IP-10), interleukin-8 (IL-8), RANTES, and peptides with hormone-like actions such as adiponectin, leptin and resistin. Through their paracrine actions these factors contribute to local WAT inflammation, neoangiogenesis and differentiation. On entering the systemic circulation they can contribute to creating or maintaining a systemic inflammatory state, hypertension and insulin resistance, and can also affect central control of food intake. When located around organs such as the kidney, heart and blood vessels, WAT can adversely affect organ function by secreting cytokines and chemokines. For example, perivascular WAT which secretes proatherogenic cytokines and chemokines and which is present around large and medium-sized arteries, could contribute to the development of atherosclerotic lesions by attracting inflammatory cells and stimulating neoangiogenesis, thereby amplifying the chronic vascular inflammation which is the hallmark of atherosclerosis.

Objective: Cytokines, platelet-activating factor (PAF), and eicosanoids control local and systemic inflammation. Conventional soybean oil-based lipid emulsions used for parenteral nutrition may aggravate the leukocyte inflammatory response or adhesion to the vessel wall. Fish oil-based lipid emulsions, in contrast, may exert an anti-inflammatory effect., Design: We investigated the impact of lipid emulsions on leukocyte invasion, protein leakage, and cytokines in two murine models of acute inflammation., Setting: Research laboratory of a university hospital., Subjects: Wild-type mice and PAF-receptor knockout mice., Interventions: Mice received an infusion of normal saline, fish oil- or soybean oil-based lipid emulsions before lipopolysaccharide challenge., Measurements and Main Results: Preinfusion with soybean oil resulted in increased leukocyte invasion, myeloperoxidase activity, and protein leakage and exaggerated release of tumor necrosis factor (TNF)-alpha as well as macrophage inflammatory protein (MIP)-2 into the alveolar space after intratracheal lipopolysaccharide challenge. In contrast, preinfusion with fish oil reduced leukocyte invasion, myeloperoxidase activity, protein leakage, and TNF-alpha as well as MIP-2 generation. Corresponding profiles were found in plasma following intraperitoneal lipopolysaccharide application: Soybean oil increased but fish oil decreased the TNF-alpha and MIP-2 formation. When PAF-receptor-deficient mice were challenged with lipopolysaccharide, leukocyte invasion, lung tissue myeloperoxidase, cytokine generation, and alveolar protein leakage corresponded to those observed in wild-type animals. Fish oil and soybean oil lost their diverging effects on leukocyte transmigration, myeloperoxidase activity, leakage response, and cytokine generation in these knockout mice. Similarly, the differential impact of both lipid emulsions on these lipopolysaccharide-provoked changes was suppressed after pretreating animals with a PAF-receptor antagonist., Conclusions: Fish oil- vs. soybean oil-based lipid infusions exert anti- vs. proinflammatory effects in murine models of acute inflammation. The PAF/PAF-receptor-linked signaling appears to be a prerequisite for this differential profile.

Chemokines were detected by virtue of chemotactic effects toward neutrophils in the late 1970s. During subsequent decades, it has become clear that their primordial role in vertebrate biology was to facilitate organogenesis, with particularly important functions in the central nervous system (CNS). In common with other developmentally relevant factors, chemokines and their G-protein-coupled receptors continue to be expressed in the adult CNS as neuromodulators. In our progress toward chemokine receptor blockade for treatment of inflammatory and infectious diseases, the CNS physiology of the chemokine system will need to be a material consideration. In some cases, the dual functions of the chemokine system in the periphery and in the CNS offer unique possibilities for disease treatment.

Chemokines play a key role in directing and driving leucocyte trafficking. The efficient regulation of leucocyte recruitment by chemokines requires their appropriate localization in functional micro-anatomical domains, as well as setting limits to their effects in space and time. Both processes are influenced by silent chemokine receptors (interceptors), including DARC (Duffy antigen receptor for chemokines). Increasing experimental evidence suggests that DARC is involved in accumulation of extravascular chemokines in endothelial cells, chemokine transcytosis and presentation on their luminal surface, leading to leucocyte adhesion and emigration. Additionally, DARC is expressed on erythrocytes and can act as a sink for chemokines in blood. This limits the dissemination of chemokines through blood into distant organs and tissues as well as reducing their effects on the circulating leucocytes.

Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.

The multistep model of leukocyte recruitment to sites of inflammation has helped elucidate specific molecular cues for each of the individual steps. However, it is less clear how cells transition between the different steps and how the complex interactions are coordinately regulated. Once a leukocyte sticks to the endothelium, it only takes a few minutes to reach the subendothelial basement membrane, so the transitions and regulatory mechanisms must be rapid. We put forward the hypothesis that proteolytic shedding of cell surface proteins provides a mechanism to aid in the rapid transition of cells and coordinate the complex, multistep process of leukocyte recruitment in response to inflammatory stimuli. Support for this hypothesis is provided from analyses of disease states and from studies with protease inhibitors and genetically engineered mutations that prevent "ectodomain shedding" of cell surface proteins and consequently perturb the inflammatory response.

Leukocyte infiltration is a cardinal feature of almost all cancers. Chemokines are generally responsible for eliciting local accumulation of inflammatory cells and they appear to play the same role in the formation of peri- and intra-tumoural infiltrates. Chronic inflammation predisposes to cancer formation and progression, and it is likely that the chemokine system contributes to this process. In part, this may be a consequence of its ability to attract mononuclear cells to cancer sites, where they provide growth or angiogenic factors that enhance cancer development. However, accumulating evidence also points to a direct effect of chemokines on cancer cells that express chemokine receptors. In particular, some chemokines can activate anti-apoptotic pathways in these cells. By either mechanism, tumour cells that secrete and/or respond to chemokines would have a selective advantage. This provides another example of cancer's ability to co-opt host systems in order to promote tumour progression.

The frequent observation of organized lymphoid structures that resemble secondary lymphoid organs in tissues that are targeted by chronic inflammatory processes, such as autoimmunity and infection, has indicated that lymphoid neogenesis might have a role in maintaining immune responses against persistent antigens. In this Review, we discuss recent progress in several aspects of lymphoid neogenesis, focusing on the similarities with lymphoid tissue development, the mechanisms of induction, functional competence and pathophysiological significance. As more information on these issues becomes available, a better understanding of the role of lymphoid neogenesis in promoting chronic inflammation might eventually lead to new strategies to target immunopathological processes.