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.

Download full-text


Available from: Kiyoshi Takatsu, Aug 19, 2014
    • "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. "
    [Show abstract] [Hide abstract]
    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 (7mg/kg) and high dose (15mg/kg) of oxyresveratrol, and methylprednisolone (15mg/kg; standard drug) was started 2week after immunization of mice with ovalbumin and continued for 7d. Ovalbumin was also injected into pinna of right ear 24h 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
    • "Because the lack of colitis observed in Csf2rb À/À mice correlated with a decrease in the frequency of eosinophils, but not neutrophils , we next investigated the relative contribution of these distinct innate effectors to the pathogenesis of colitis. We employed two strategies to deplete eosinophils, either blockade of the eosinopoietin IL-5 (Kouro and Takatsu, 2009) or antibody-mediated depletion of Siglec-F + cells. In the presence of IL-10R blockade, Hh infected mice treated with anti-IL-5 had a 50% reduction in total cLPL compared to isotype treated controls (data not shown) and an 87% decrease in the percentage "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.
    Immunity 07/2015; Volume 43(1):187-99. DOI:10.1016/j.immuni.2015.07.008. · 21.56 Impact Factor
  • Source
    • "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). "
    Dataset: 000

Show more