IL-5- and eosinophil-mediated inflammation: From discovery to therapy

Laboratory of Immune Modulation, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
International Immunology (Impact Factor: 3.18). 10/2009; 21(12):1303-9. DOI: 10.1093/intimm/dxp102
Source: PubMed

ABSTRACT IL-5 was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells, at least in mice. Concurrently, IL-5 was recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Over-expression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo. Conversely, mice lacking a functional gene for IL-5 or the IL-5 receptor alpha chain (IL-5Ralpha) display a number of developmental and functional impairments in B-cell and eosinophil lineages. In addition to the Janus kinase-signal transducer and activator of transcription pathway, the tyrosine kinases Lyn and Btk (Bruton agammaglobulinemia tyrosine kinase) are involved, and Ras GTPase-extracellular signal-regulated kinase (Ras-ERK) signals are important for IL-5-dependent cell proliferation and survival. IL-5 critically regulates expression of genes involved in proliferation, cell survival and maturation and effector functions of B cells and eosinophils. Thus, IL-5 plays a pivotal role in innate and acquired immune responses and eosinophilia. In humans, the biologic effects of IL-5 are best characterized for eosinophils. The recent expansion in our understanding of the mechanisms of eosinophil development and activation in the context of IL-5 has led to advances in therapeutic options. A new therapy currently in clinical trials uses humanized mAbs against IL-5 or the IL-5R.

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Available from: Kiyoshi Takatsu, Aug 19, 2014
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    • "Over-expression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo (Kouro & Takatsu, 2009). IL-5 induces terminal maturation of eosinophils, prolongs eosinophil survival by delaying apoptotic death, possesses eosinophil chemotactic activity, increases eosinophil adhesion to endothelial cells and enhances eosinophil effector functions (Kouro & Takatsu, 2009). "
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    • "In humans, IL-5 is best characterized as a major maturation and differentiation factor for eosinophils [13]. Because of the importance of eosinophils for allergy and other associated disorders, IL-5 has been proposed as a potential molecular target for the treatment of these diseases, with a couple of IL-5 antagonist therapies currently under development [13] [14]. Prior to the recent gene-centric study in CAD [11], the role of IL-5 in CVD had been barely touched upon, with one publication linking plasma IL-5 levels inversely to subclinical atherosclerosis [15] and two studies implicating raised IL-5 levels in unstable angina and myocardial infarction [16] and risk of recurrent CAD events [17]. "
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    ABSTRACT: Genetic variants robustly associated with coronary artery disease were reported in the vicinity of the interleukin (IL)-5 locus, and animal studies suggested a protective role for IL-5 in atherosclerosis. Therefore, we set this work to explore IL-5 as a plasma biomarker for early subclinical atherosclerosis, as determined by measures of baseline severity and change over time of carotid intima-media thickness (cIMT). We used biobank and databases of IMPROVE, a large European prospective cohort study of high-risk individuals (n = 3534) free of clinically overt cardiovascular disease at enrollment, in whom composite and segment-specific measures of cIMT were recorded at baseline and after 15 and 30 months. IL-5 was measured with an immunoassay in plasma samples taken at baseline. IL-5 levels were lower in women than in men, lower in the South than in North of Europe, and showed positive correlations with most established risk factors. IL-5 showed significant inverse relationships with cIMT change over time in the common carotid segment in women, but no significant relationships to baseline cIMT in either men or women. Our results suggest that IL-5 may be part of protective mechanisms operating in early atherosclerosis, at least in women. However, the relationships are weak and whereas IL-5 has been proposed as a potential molecular target to treat allergies, it is difficult to envisage such a scenario in coronary artery disease. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Atherosclerosis 12/2014; 239(1):125-130. DOI:10.1016/j.atherosclerosis.2014.12.046 · 3.97 Impact Factor
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    • "IL-5 is a typical cytokine produced by Th2 cells, playing a central role in differentiation and in the activation of eosinophils. Further, IL-5 triggers B-cell differentiation into antibody-producing plasma cells [Kouro and Takatsu, 2009]. During the acute phase, suppression of IL-5 production below control levels indicates the existence of Th1 (cell-mediated) proinflammatory polarization of the host immune response during TBE neuroinfection. "
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    ABSTRACT: Tick-borne encephalitis (TBE) is a leading human neuroinfection in Europe and northeastern Asia. However, the pathophysiology of TBE is not understood completely. This study sought to determine the specific serum mediators that are associated with acute TBE. The levels of 30 cytokines, chemokines, and growth factors were measured in serum samples from 87 patients with clinically and serologically confirmed acute TBE and from 32 control subjects using the Cytokine Human Magnetic 30-Plex Panel for the Luminex platform. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were measured via enzyme-linked immunosorbent assay. TBE virus infection elicited increased levels of the pro-inflammatory cytokines interleukin (IL)-6, IL-8, and IL-12. TBE patients had higher IL-12:IL-4 and IL-12:IL-10 ratios than control patients, reflecting the global pro-inflammatory cytokine balance. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were significantly lower in TBE patients than in the control group. Most interestingly, increased levels of hepatocyte growth factor andvascular endothelial growth factor were observed in TBE patients; these proteins may be novel and mechanistically important inflammatory biomarkers of TBE.
    Journal of Medical Virology 12/2014; 87(5). DOI:10.1002/jmv.24140 · 2.22 Impact Factor
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