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 2

HRF-reactive Igs binds HRF via their Fab region.

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HRF-reactive Igs binds HRF via their Fab region. (A and B) Fab, but not ...
(A and B) Fab, but not Fc, fragments bound to HRF. GST-mHRF was coated onto a 96-well ELISA plate. After blocking with 10% FCS, the plate was incubated with whole molecules (IgG) or with Fab or Fc fragments of the indicated IgGs. HRF-bound Fab was detected by incubation with HRP-conjugated goat anti-mouse κ chain antibody. HRF-bound Fc or IgG was detected with HRP-conjugated anti-IgG. (C and D) Competition by Fab, but not Fc, fragments for JK17 IgG binding to HRF. GST-mHRF was incubated with JK17 IgG in the presence or absence of Fab or Fc fragments at different molar ratios. Bound JK17 IgG was detected with HRP-conjugated anti-κ (C) or biotin-conjugated anti-IgG1 followed by streptavidin-HRP (D). (E and F) Competition by Fab, but not Fc, fragments for C38-2 IgE binding to HRF. GST-mHRF was incubated with C38-2 IgE in the presence or absence of Fab or Fc fragments at different molar ratios. Bound IgE was detected with biotin-conjugated anti-mouse IgE followed by streptavidin-HRP. *P < 0.05. All data are representative of 2 experiments.