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Inhibitory Role of IGFBP-3 in the Pathogenesis of Asthma« Back to Volume 26, Issue 1, September 2010 - Table of Contents From ENDO 2010 The Endocrine Society Annual Meeting, San Diego, June 19-22, 2010 Insulin-like growth factor-binding protein (IGFBP)-3 is a multi-functional protein known for modulating the actions of insulin-like growth factors (IGFs) in somatic growth and a variety of human diseases such as cancer. Despite the critical role of the IGF system in the pathophysiology of many diseases, limited information is available for its role in bronchial asthma. IGFBP-3 fragments have been identified in asthmatic airway tissue extracts. Whether there is any association between IGFBP-3 and asthma remains elusive. The researchers performed in vitro and in vivo studies to show that IGFBP-3 blocks specific physiological consequences of asthma in an IGF-independent manner. They used a mouse asthma model with normal mice as well as IGFBP-3 transgenic mice challenged to ovalbumin (OVA). The results show IGFBP-3 suppressed in bronchial epithelial cells from normal mice after OVA challenge. Restoration of IGFBP-3 either by recombinant IGFBP-3 treatment or adenoviral IGFBP-3 gene transfer effectively reduced all physiological manifestations of asthma examined in vivo (airway hyperresponsiveness [AHR], cellular and pathological change in bronchoalveolar lavage [BAL] fluid and lung tissue, and expression of numerous proinflammatory molecules). Furthermore, IGFBP-3 treatment restored airway functions as demonstrated by the reduction of OVA-induced AHR. These unique IGFBP-3 effects were IGF/IGF-I receptor (IGF-IR) independent since IGFBP-3 mutant devoid of IGF binding affinity (IGFBP-3 GGG) had similar effects. The studies using IGFBP-3 transgenic mice further confirmed the effects of IGFBP-3 by demonstrating significant reduction of infiltration of inflammatory cells, cytokine production and OVA-induced AHR compared to that of normal mice after OVA inhalation. Further in vitro studies using human bronchial epithelial cells demonstrated that IGFBP-3 blocks TNF-α-induced expression of proinflammatory molecules, attenuates the TNF-α-induced migratory response of eosinophils, and negatively regulates TNF-α-induced expression of the key NF-κB regulatory molecules, IκBα and p65-NF-κB, at the post-translational level. Taken together, these results strongly indicated that IGFBP-3 inhibits airway inflammation and airway hyperresponsiveness via an IGF-independent mechanism that involves cross-talk with NF-κB pathway. IGFBP-3 therefore plays a pivotal role in the pathogenesis of asthma, and thus can serve as a potential therapeutic for prevention/treatment of asthma. Lee Y, Jogie-Brahim S, Harada A, et al. Chonbuk National University, Jeonju, Republic of Korea; University of Manitoba Winnipeg, Canada; and Virginia Commonwealth University, Richmond, Virginia, USA Editor's CommentThis is a new and interesting view into the pathogenesis of this common disease. IGF-I is known to be involved in airway remodeling in bronchial epithelial cells; interleukin (IL)-17F is able to induce the expression of IGF-I via the Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB pathway in vitro.1 Another mechanism of allergic airway remodeling may also be via the secretion of the profibrotic IGFBP-3 from IGF-I-stimulated airway epithelial cells during allergic inflammation.2 Of interest may be the potential role of the IGF system alterations in allergic disease and asthma in growth retardation. The prevalence of short stature (< 3rd percentile NCHS) among children with respiratory allergy (asthma and/or rhinitis) varies from 2−10%. Hauache et al3 studied IGF-I, IGFBP-3, and growth hormone (GH) serum levels after stimulation tests in prepubertal allergic boys who had not received steroids. All children were short and had delayed skeletal age in relation to chronological age, but bone age was normal for height. The serum levels of IGF-I, IGFBP-3, and GH after stimulation tests were normal and they concluded that in these children a deficiency of GH did not seem to be responsible for short stature. Fima Lifshitz, MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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