1,721,126 research outputs found
Molecular pathways and targets in cancer-related inflammation
No full textSelected inflammatory conditions increase the risk of cancer. An inflammatory component is present also in the micro-environment of tumours epidemiologically unrelated to inflammation. 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 contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, response to hormones, and chemotherapeutic agents. Emerging evidence also suggests that cancer-related inflammation promotes genetic instability. Thus, cancer-related inflammation represents a target for innovative diagnostic and therapeutic strategies
TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization
No full textTIR8, also known as single Ig IL-1 receptor (IL-R)-related molecule, SIGIRR, is a member of the IL-1R like (ILR) family. Unlike most other members of this family, it has a single extracellular Ig domain, a long cytoplasmic tail and a Toll/IL-1R (TIR) domain with two amino acid substitutions possibly consistent with non-conventional signaling. The TIR8 structure and pattern of expression are conserved in evolution from birds to humans. Current evidence suggests that TIR8 inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33) and Th17 (IL-1) differentiation. TIR8 also dampens TLR-mediated activation. The ability to dampen signaling from ILR family members and TLRs makes TIR8 a key regulator of inflammation, cancer-related inflammation, and autoimmunity
Macrophage diversity and polarization in atherosclerosis: a question of balance
No full textDiversity and plasticity are hallmarks of mononuclear phagocytes, which are reflected in plaque formation and evolution. Different monocyte subsets, which differentially contribute to plaque infiltration and to atherosclerosis complications, have been identified. Similarly, depending on different environmental signals plaque-associated macrophages can express polarized pro- and antiatherogenic programs by influencing lipid metabolism, inflammatory responses, and plaque stability. Thus, a "macrophage balance" plays a major role in the pathogenesis of atherosclerotic plaques and affects evolution and complications of atherosclerosis
Inflammation-mediated promotion of invasion and metastasis
No full textInflammation has been suggested to represent the seventh hallmark of cancer. Myelomonocytic cells are a key component of cancer-related inflammation. Tumor-associated macrophages and their mediators affect key elements in the multistep process of invasion and metastasis, from interaction with the extracellular matrix to the construction of a pre-metastatic niche. Evidence indicating that inflammatory mediators affect genetic stability and cause persistent epigenetic alterations suggests that inflammatory components of the tumor microenvironment impacts on fundamental mechanisms responsible for the generation of metastatic variants. These results provide impetus for efforts aimed at translating cancer-related inflammation into diagnostic-prognostic markers and innovative therapeutic strategies
An integrated view of humoral innate immunity : pentraxins as a paradigm
No full textThe innate immune system consists of a cellular and a humoral arm. Pentraxins (e.g., the short pentraxin C reactive protein and the long pentraxin PTX3) are key components of the humoral arm of innate immunity which also includes complement components, collectins, and ficolins. In response to microorganisms and tissue damage, neutrophils, macrophages, and dendritic cells are major sources of fluid-phase pattern-recognition molecules (PRMs) belonging to different molecular classes. Humoral PRMs in turn interact with and regulate cellular effectors. Effector mechanisms of the Immoral innate immune system include activation and regulation of the complement cascade; agglutination and neutralization; facilitation of recognition via cellular receptors (opsonization); and regulation of inflammation. Thus, the humoral arm of innate immunity is an integrated system consisting of different molecules and sharing functional outputs with antibodies
DEFICIENCY OF THE SOLUBLE PATTERN RECOGNITION RECEPTOR PENTRAXIN-3 INCREASES SUSCEPTIBILITY TO TUMOR GROWTH AND METASTASIS
No full textThe long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor involved in innate immunity, inflammation, tissue remodelling and female fertility. Moreover PTX3 binds fibroblast growth factor-2 (FGF-2) and inhibits its angiogenic activity. PTX3 is elevated in several pathological conditions reflecting in particular the involvement of the vascular bed as ischemic heart disease, atherosclerosis, small vessel vasculitis and preeclampsia. PTX3 plasma levels are elevated in cancer patients, such as in soft tissue liposarcoma and chondrosarcoma. As PTX3 is a structural component of the cumulus oophorus extracellular matrix in human and mouse, through the interaction with hyaluronic acid binding proteins TNF- α -stimulated gene-6 (TSG-6) and inter-α-trypsin inhibitor (IαI), we hypothesized that PTX3 could be a component of other extracellular matrices such as in the tumor stroma. Moreover, being produced by tumor stromal cells (endothelial cells, fibroblasts, leukocytes), PTX3 could play a role in modulating inflammation associated with tumor growth. To address the involvement of PTX3 in tumor growth, we used a model of non immunogenic and metastatic murine fibrosarcoma (MN/MCA1) and we observed an increased tumor growth and metastatic potential associated with PTX3 deficiency. Moreover in a model of immunogenic fibrosarcoma (MCA203) we observed an accelerated tumor growth in PTX3 knock out mice compared to wild type mice. Mechanisms potentially involved in the mentioned phenotypes range from regulation of angiogenesis and inflammation to organization of the extracellular matrix (ECM) through the direct interaction with ECM components and are currently under investigation. The preliminary results obtained in this study suggest that PTX3 could be a potential therapeutic target in tumor growth
The long pentraxin PTX3 : a modulator of the immunoinflammatory response in atherosclerosis and cardiovascular diseases
No full textInnate and adaptive immune responses participate in atherosclerosis. Pentraxins, an essential component of the humoral arm of innate immunity, are a superfamily of acute phase proteins highly conserved during evolution and can be classified as short pentraxins such as C-reactive protein (CRP) and long pentraxins such as PTX3. The latter has an unrelated, long N-terminal domain coupled to the C-terminal pentraxin domain and differs from CRP in gene organization, cellular source, and recognized ligands. PTX3 in humans, like CRP, is a marker of atherosclerosis and correlates with the risk of developing vascular events. Although CRP sequence and regulation have not been conserved during evolution between mouse and man, the conservation of sequence, gene organization, and regulation of PTX3 in evolution enables one to address the question regarding its pathophysiologic roles in genetically modified mice. Deficiency of PTX3 is associated with increased heart damage with a greater no-reflow area and increased inflammatory response in a model of acute myocardial infarction (MI) caused by coronary artery ligation. More recently, deficiency of PTX3 on an apolipoprotein E knockout background was associated with increased atherosclerosis, macrophage accumulation within the plaque, and a more pronounced inflammatory profile in the vascular wall. Although these observations point to a cardiovascular protective effect of PTX3, they also suggest the possibility that the increased levels of PTX3 in subjects with cardiovascular disease (CVD) may reflect a protective physiologic response that correlates with the severity of the disease. In summary, data that are accumulating suggest that the increase of pentraxins in atherosclerosis could not be regarded as a harmful response but rather a further attempt to protection of our body
Negative regulatory receptors of the IL-1 family
No full textThe IL-1 family of ligands and receptors has a central role in both innate and adaptive immune responses and is tightly controlled by antagonists, decoy receptors, scavengers, dominant negative molecules, miRNAs and other mechanisms, acting extracellularly or intracellularly. During evolution, the development of multiple mechanisms of negative regulation reveals the need for tight control of the biological consequences of IL-1 family ligands in order to balance local and systemic inflammation and limit immunopathology. Indeed, studies with gene targeted mice for negative regulators and genetic studies in humans provide evidence for their non-redundant role in controlling inflammation, tissue damage and adaptive responses. In addition, studies have revealed the need of negative regulation of the IL-1 family not only in disease, but also in homeostatic conditions. In this review, the negative regulation mediated by decoy receptors are presented and include IL-1R2 and IL-IL-18BP as well as atypical receptors, which include TIR8/SIGIRR, IL-1RAcPb, TIGIRR-1 and IL-1RAPL. Particular emphasis is given to IL-1R2, since its discovery is the basis for the formulation of the decoy paradigm, now considered a general strategy to counter the primary inflammatory activities of cytokines and chemokines. Emphasis is also given to TIR8, a prototypical negative regulatory receptor having non-redundant roles in limiting inflammation and adaptive responses
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