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      Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development

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          Abstract

          Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF- α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

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          Historical insights into cytokines.

          Cytokines affect nearly every biological process; these include embryonic development, disease pathogenesis, non-specific response to infection, specific response to antigen, changes in cognitive functions and progression of the degenerative processes of aging. In addition, cytokines are part of stem cell differentiation, vaccine efficacy and allograft rejection. This short insight focuses on the milestones in cytokine biology and how the various and often contradictory activities of these small, non-structural proteins affected the fields of inflammation and immunology. Multiple biological properties or pleiotropism is the hallmark of a cytokine. Today, the term "cytokine" encompasses interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. As of this writing, 33 cytokines are called interleukins, but many are part of families of related but distinct gene products. There are certainly over 100 separate genes coding for cytokine-like activities, many with overlapping functions and many still unexplored. Also discussed in this overview are the failures and successes of cytokines as therapeutic targets. A recent advance in the field has been that of differential cytokine production, which can be used to classify human disease as being "autoimmune" or "autoinflammatory" thus impacting on therapeutic interventions.
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            Inflammatory mediators in the elderly.

            Ageing is accompanied by 2-4-fold increases in plasma/serum levels of inflammatory mediators such as cytokines and acute phase proteins. A wide range of factors seems to contribute to this low-grade inflammation, including an increased amount of fat tissue, decreased production of sex steroids, smoking, subclinical infections (e.g. asymptomatic bacteriuria), and chronic disorders such as cardiovascular diseases and Alzheimer's disease. Furthermore, there is some evidence that ageing is associated with a dysregulated cytokine response following stimulation. Several inflammatory mediators such as tumour necrosis factor-alpha and interleukin-6 have the potential to induce/aggravate risk factors in age-associated pathology, providing a positive feedback mechanism. Thus, it is possible that inflammatory mediators constitute a link between life style factors, infections and physiological changes in the process of ageing on the one hand and risk factors for age-associated diseases on the other. Consistent with this, inflammatory mediators are strong predictors of mortality independently of other known risk factors and co-morbidity in elderly cohorts. A direct pathogenetic role of inflammatory mediators would be highly likely if longevity was shown to be associated with cytokine polymorphisms regulating cytokine production. Several studies support indeed this hypothesis but, unfortunately, findings in this area are conflicting, which probably reflects the complexity of the effect of cytokine polymorphisms and their interaction with the lifestyle and sex.
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              Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study.

              Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance. Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines. In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories. This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2015
                11 October 2015
                : 2015
                : 284706
                Affiliations
                1Division of Hospital Internal Medicine, Mayo Clinic, Scottsdale, AZ 85054, USA
                2Department of Statistics, Mayo Clinic, Scottsdale, AZ 85054, USA
                3Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA
                Author notes

                Academic Editor: Sylvie Hermouet

                Article
                10.1155/2015/284706
                4619953
                26538823
                124d76a1-cfd0-4654-89b5-e6a59b979146
                Copyright © 2015 Holly L. Geyer et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 June 2015
                : 9 August 2015
                Categories
                Review Article

                Immunology
                Immunology

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