Insulin-like Growth Factor-binding Protein-3 (IGFBP-3) Blocks the Effects of Asthma by Negatively Regulating NF-κB Signaling through IGFBP-3R-mediated Activation of Caspases

Yong-Chul Lee,Sherryline Jogie-Brahim,Dae-Yeol Lee,Jinfeng Han,Aki Harada,Liam J Murphy,Youngman Oh

doi:10.1074/jbc.m111.231035

Abstract

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein known for modulating mitogenic and metabolic actions of IGFs as well as exerting a variety of biological actions not involving IGFs. Here, we show that IGFBP-3 blocks specific physiological consequences of asthma in an IGF-independent manner in vitro and in vivo. IGFBP-3 treatment effectively reduced all physiological manifestations of asthma examined in vivo (airway hyper-responsiveness, cellular and pathological changes in bronchoalveolar lavage fluid and lung tissue, and expression of numerous proinflammatory molecules). These unique IGFBP-3 effects were further confirmed in IGFBP-3-transgenic mice, thus strengthening the notion of IGFBP-3 actions within the respiratory system. Using human epithelial cells, we demonstrated the following: 1) IGFBP-3 blocks TNF-α-induced expression of proinflammatory molecules; 2) IGFBP-3 attenuates the TNF-α-induced migratory response of eosinophils; and 3) IGFBP-3 negatively regulates TNF-α-induced expression of the key NF-κB regulatory molecules IκBα and p65-NF-κB at the post-translational level. We identified that IGFBP-3 degrades IκBα and p65-NF-κB proteins through IGFBP-3 receptor (IGFBP-3R)-mediated activation of caspases thereby inhibiting TNF-α-induced activation of NF-κB signaling cascades. This unique IGFBP-3/IGFBP-3R action was further confirmed by demonstrating complete inhibition of IGFBP-3 action in the presence of caspase inhibitors as well as IGFBP-3R siRNAs. Non-IGF-binding IGFBP-3 mutants further proved the IGF-independent action of IGFBP-3. Our findings indicate that IGFBP-3 inhibits airway inflammation and hyper-responsiveness via an IGF-independent mechanism that involves activation of IGFBP-3R signaling and cross-talk with NF-κB signaling. The IGFBP-3/IGFBP-3R system therefore plays a pivotal role in the pathogenesis of asthma and can serve as a newly identified potential therapeutic target for this debilitating disease.

Highlights

Bronchial asthma is one of the most common chronic inflammatory diseases in modern society, and yet, despite the availability of current drugs, its incidence is increasing [16]
Effect of IGFBP-3 and IGFBP-3GGG Mutant on Pathological Changes of OVA-induced Asthma—Because inflammatory cell recruitment is a hallmark phenomenon of all inflammatory diseases, including asthma [30], we assessed the population of total cells, lymphocytes, neutrophils, and eosinophils in Bronchoalveolar lavage (BAL) fluids obtained from normal (Fig. 2A) and IGFBP-3 transgenic mice (Fig. 2B)
Recent clinical studies suggested a role for IGFBP-3 on the pathogenesis of inflammatory diseases by demonstrating that serum IGFBP-3 was significantly decreased in patients with a variety of inflammatory diseases, including juvenile idiopathic arthritis, rheumatoid arthritis, pulmonary sarcoidosis, cystic fibrosis, Crohn disease, and inflammatory bowel disease [35,36,37,38,39,40], and when disease was in remission, the serum IGFBP-3 reached normal levels [39, 40]

Summary

Introduction

Bronchial asthma is one of the most common chronic inflammatory diseases in modern society, and yet, despite the availability of current drugs, its incidence is increasing [16]. IGFBP-3 did not induce any change in mRNA levels of I␬B␣ and p65-NF-␬B in bronchial epithelial cells, suggesting posttranscriptional effects (supplemental Fig. S4).

Results

Conclusion