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 3

Mapping IgE-binding sites within HRF and inhibition of HRF-IgE interactions by the HRF-derived N19 and H3 peptides.

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Mapping IgE-binding sites within HRF and inhibition of HRF-IgE interacti...
(A) Scheme of full-length (FL) and truncated forms of GST-mHRF used for binding assays. Domain structures such as TCTP1–TCTP2 and H1–H3 are shown. (B) IgE-binding site mapping. C38-2 (5 μg/ml) and αOE (20 μg/ml) IgE molecules were incubated in wells coated with GST-mHRF. Bound Igs were detected by ELISA. <0.1, value too small to display. (C) Inhibition of HRF-Ig interactions by N19. IgE molecules were incubated in GST-mHRF–coated wells in the presence or absence of the indicated concentrations of competitors. After incubation, bound IgE was detected by ELISA. (D) Inhibition of HRF-Ig interactions by GST-H3. *P < 0.05, **P < 0.01. Data are representative of 2 (B), 5 (C), or 3 (D) experiments.