Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy
Jun-ichi Kashiwakura, Tomoaki Ando, Kenji Matsumoto, Miho Kimura, Jiro Kitaura, Michael H. Matho, Dirk M. Zajonc, Tomomitsu Ozeki, Chisei Ra, Susan M. MacDonald, Reuben P. Siraganian, David H. Broide, Yuko Kawakami, Toshiaki Kawakami
Jun-ichi Kashiwakura, Tomoaki Ando, Kenji Matsumoto, Miho Kimura, Jiro Kitaura, Michael H. Matho, Dirk M. Zajonc, Tomomitsu Ozeki, Chisei Ra, Susan M. MacDonald, Reuben P. Siraganian, David H. Broide, Yuko Kawakami, Toshiaki Kawakami
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Research Article Immunology

Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy

Abstract

IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/HRF-induced mast cell activation and in vivo cutaneous anaphylaxis and airway inflammation. Intranasally administered HRF recruited inflammatory immune cells to the lung in naive mice in a mast cell– and Fc receptor–dependent manner. These results indicate that HRF has a proinflammatory role in asthma and skin immediate hypersensitivity, leading us to suggest HRF as a potential therapeutic target.

Authors

Jun-ichi Kashiwakura, Tomoaki Ando, Kenji Matsumoto, Miho Kimura, Jiro Kitaura, Michael H. Matho, Dirk M. Zajonc, Tomomitsu Ozeki, Chisei Ra, Susan M. MacDonald, Reuben P. Siraganian, David H. Broide, Yuko Kawakami, Toshiaki Kawakami

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Figure 6

GST-N19 blocks mast cell–dependent airway inflammation.

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GST-N19 blocks mast cell–dependent airway inflammation. C57BL/6 mice wer...
C57BL/6 mice were sensitized with OVA (10 μg) and i.n. challenged with OVA (20 μg) or PBS. Some mice were i.n. pretreated with GST or GST-N19 (400 μg) before every OVA challenge. 24 hours after the last challenge, mice were subjected to invasive lung function testing, and BAL fluids and lung tissues were collected. (A) Increased HRF amounts in the lung and sera of OVA-sensitized and -challenged mice. SDS-PAGE was performed on lung homogenates and serum samples, and HRF amounts of 3 mice were evaluated by immunoblotting. ERK1/2 expression was used as a loading control. (B) Total and specific immune cell numbers in BAL fluids. Eos, eosinophils; Neu, neutrophils; Lym, lymphocytes; MΦ, macrophages and monocytes. (C) H&E and periodic acid-Schiff (PAS) staining of lung tissues. Scale bars: 200 μm. (D) IL-5 and IL-13 in lung homogenates were measured by ELISA. (E) Airway resistance was measured using FlexiVent. *P < 0.05, **P < 0.01, ***P < 0.001. 3–6 mice were used for each cohort. All data are representative of 3 experiments.