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: 2.54). 10/2009; 21(12):1303-9. DOI: 10.1093/intimm/dxp102
Source: PubMed


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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    • "Eosinophils in turn produce bronchoconstriction and odema by releasing lipid mediators and cause tissue destruction by secreting enzymes [13]. These effects along with the release of inflammatory cytokines might play an important role in remodeling of lungs in chronic asthma [6] [10]. Glucocorticosteroids are the most routinely prescribed antiinflammatory agents in asthma. "
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    ABSTRACT: Aim Oxyresveratrol is known to possess anti-inflammatory property. Current study investigates the immunosuppressive effect of oxyresveratrol by using mouse model of ovalbumin (OVA)-induced allergic airway inflammation. Methods BALB/c mice were randomly divided into five groups having 8 mice in each group. Treatment with low dose (7 mg/kg) and high dose (15 mg/kg) of oxyresveratrol, and methylprednisolone (15 mg/kg; standard drug) was started 2 week after immunization of mice with ovalbumin and continued for 7 d. Ovalbumin was also injected into pinna of right ear 24 h before sacrificing the mice to evaluate delayed type hypersensitivity (DTH). H&E and PAS staining were used for histopathological evaluation of lungs. Reverse transcription polymerase chain reaction followed by gel electrophoresis were used for evaluation of mRNA expression levels of IL-4, IL-5, and IL-13. Results Oxyresveratrol significantly reduced total leucocyte count in both blood and bronchoalveolar lavage fluid (BALF). Treatment with oxyresveratrol normalized altered eosinophil and neutrophil counts in both blood and BALF. OVA-specific T-cell response was also significantly inhibited by oxyresveratrol. A significant attenuation of inflammatory cell infiltration and goblet cell hyperplasia was observed after treatment with oxyresveratrol. Data showed that oxyresveratrol significantly suppressed Th2 (T helper cells) type immune response which was obvious by the reduction in mRNA expression levels of IL-4, IL-5, and IL-13. Similarly, treatment with methylprednisolone also significantly reduced all the immunomodulatory and inflammatory parameters. Conclusions Our study demonstrates that oxyresveratrol ameliorates allergic asthma. The anti-asthmatic activity might in part occur via the down regulation of IL-4, IL-5, and IL-13 expression levels.
    Cytokine 10/2015; DOI:10.1016/j.cyto.2015.09.013 · 2.66 Impact Factor
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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 · 3.99 Impact Factor
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