Th2 cytokines and asthma — Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists

Abstract

FEV 1 = forced expiratory volume in 1 second; GCR = glucocorticoid receptor; IL = interleukin; IL-4R = interleukin-4 receptor; IRS = insulin receptor substrate; rhuIL-4R = soluble recombinant human interleukin-4 receptor; Stat = signal transducer and activator of transcription; VCAM = vascular cell adhesion molecule.Available online http://respiratory-research.com/content/2/2/066 Introduction Interleukin (IL)-4 is a key cytokine in the development of allergic inflammation. It is associated with induction of the ε isotype switch and secretion of IgE by B lymphocytes [1]. IgE-mediated immune responses are further enhanced by IL-4 through its ability to upregulate IgE receptors on the cell surface: the low-affinity IgE receptor (FcεRII; CD23) on B lymphocytes and mononuclear phagocytic cells and the high-affinity IgE receptor (FcεRI) on mast cells and basophils [2]. IgE-dependent mast cell activation induced by IL-4 has a pivotal role in the development of immediate allergic reactions. An additional mechanism by which IL-4 contributes to airway obstruction in asthma is through the induction of mucin gene expression and the hypersecretion of mucus [3]. IL-4 increases the expression of eotaxin and other inflammatory cytokines from fibroblasts that might contribute to inflammation and lung remodelling in chronic asthma [4].An important activity of IL-4 in promoting cellular inflammation in the asthmatic lung is the induction of vascular cell adhesion molecule (VCAM)-1 on vascular endothelium [5]. Through the interaction of VCAM-1, IL-4 is able to direct the migration of T lymphocytes, monocytes, basophils, and eosinophils to inflammatory loci. In addition, IL-4 inhibits eosinophil apoptosis and promotes eosinophilic inflammation by inducing eosinophil chemotaxis and activation through the increased expression of eotaxin [6].An essential biological activity of IL-4 in the development of allergic inflammation is the ability to drive the differentiation of naive T helper type 0 (T H 0) lymphocytes into T H 2 lymphocytes [7,8]. These T H 2 cells are able to secrete IL-4, IL-5, IL-9 and IL-13 but lose the ability to produce interferon-γ AbstractInterleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.

Reduced FcεRI-Mediated Release of Asthma-Promoting Cytokines and Chemokines from Human Basophils during Omalizumab Therapy

“…IL-4 plays important pro-inflammatory functions in asthma including inducing the IgE isotype switch, increasing expression of vascular cell adhesion molecule-1, promoting eosinophil transmigration across endothelium, enhancing mucus secretion, and stimulating differentiation of Th2 lymphocytes leading to further cytokine synthesis and release [32,33,34,35]. IL-13 also causes Th2 cell differentiation and IgE production and induces many other features of allergic lung disease, including airway hyperresponsiveness, goblet cell metaplasia and mucus hypersecretion [32,36].…”

Enhancement of Interleukin-4 Production in Activated CD4+ T Cells by Diphthalate Plasticizers via Increased NF-AT Binding Activity

“…IL-4 may also contribute to airway obstruction in asthma through its capability to induce mucin gene expression. Thus, IL-4 plays a key role in the development of allergic inflammation [11]. …”

An Experimental Study to Evaluate the Anti-inflammatory and Immunmodulatory Effects of UNIM-352, a Polyherbal Preparation for Bronchial asthma

“…The Th2 derived cytokine, IL-4 plays an important pro-inflammatory function in asthma which includes induction of the IgE isotype switch, expression of the vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of Th2 lymphocytes leading to cytokine release ( Steinke and Borish, 2001;Moser and Fehr, 2002;Mahajan and Mehta, 2006 have both immunomodulatory and anti-inflammatory role in preventing airway inflammation by significantly reducing the levels of the Th2 derived cytokine (IL-4) as well the pro-inflammatory markers (TNF-α and IL-1β)-all of which play key roles in the pathophysiology of allergic asthma. It is also interesting to note that these changes induced by the polyherbal agent were comparable to that of prednisolone (the reference drug) in the markers of inflammation and immunity in our experiments.…”

“…Mast cell mediated hypersensitivity reactions to allergens are involved in the pathogenesis of such asthma and their activation triggers the process of degranulation and release of mediators like histamine and an array of inflammatory cytokines. Both pro-and anti-inflammatory cytokines determine the extent and progress of airway inflammation and their interactions with modulators like histamine and leukotrienes determine the severity of the disease (Withers et al, 1998;Steinke and Borish, 2001;Mahajan and Mehta, 2006). Although corticosteroids are effective as nonspecific antiinflammatory agents, the side effects of corticosteroid treatment are of significant concern (Akinbami and Schoendorf, 2002;Steurer-Stey et al, 2002).…”