Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy
Jun-ichi Kashiwakura, … , Yuko Kawakami, Toshiaki Kawakami
Jun-ichi Kashiwakura, … , Yuko Kawakami, Toshiaki Kawakami
Published December 1, 2011
Citation Information: J Clin Invest. 2012;122(1):218-228. https://doi.org/10.1172/JCI59072.
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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 1

A subset of IgE and IgG molecules binds HRF.

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A subset of IgE and IgG molecules binds HRF. (A) IgE molecules were incu...
(A) IgE molecules were incubated in GST-mHRF–coated wells. HRF-bound IgE was quantified by ELISA, as detected by color development with HRP. OD450 values with GST-mHRF subtracted from those with GST control are shown. OD450 ≤ 0.1 was used as an arbitrary cutoff value. Data represent at least 3 experiments. (B) IgEs were incubated with GST- or GST-mHRF–agarose beads. Bead-bound IgEs were pulled down. IgE and GST proteins were detected by immunoblotting. Lanes were run on the same gel but were noncontiguous (white lines). Representative of 2 experiments. (C) BMMCs preincubated with (black line) or without (gray shading) the indicated IgE (see Supplemental Table 3) were incubated with mHRF-His6, and bound mHRF-His6 was detected with rabbit anti-His tag antibody and Alexa Fluor 647–conjugated anti-rabbit IgG. HRF binding was detected by flow cytometry. Insets show IgE binding: the same cells were incubated with FITC-labeled anti-mouse IgE. Representative of 2 experiments. (D) HRF-bound IgGs were detected by ELISA. Representative of 3 experiments. HRF binding was independent of IgG isotype, as the tested IgG1, IgG2a, and IgG2b molecules contained both HRF-reactive and -nonreactive molecules. The KD values for HRF binding were 0.685 μM (JK17), 2.78 μM (JK31), and 5.78 μM (JK96). Black bars, IgG1; white bars, IgG2a; gray bars, IgG2b.