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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 10

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

×

Figure 5

HRF promotes PCA reactions in mice sensitized with HRF-reactive IgE.

Options: View larger image (or click on image) Download as PowerPoint
HRF promotes PCA reactions in mice sensitized with HRF-reactive IgE. (A)...
(A) IgE/HRF-induced acute PCA reactions. Mice were sensitized with the indicated IgEs. 24 hours later, Evans blue and mHRF-His6 were injected in IgE-sensitized mice. After 30 minutes, dye leakage from the ears was measured. For controls, saline (Sal) and TNP26-BSA (Ag) were injected in sensitized ears. KitW–sh/W–sh mice were used before or 6 weeks after engraftment of WT BMMCs by i.d. injection. Toluidine blue staining confirmed that the engrafted mice had numbers of mast cells similar to those of WT mice. (B–D) IgE/HRF-induced PCA LPRs. mHRF-His6 was injected in IgE-sensitized ears, and LPR was analyzed by measurement of ear thickness at 6 hours. For controls, saline and TNP26-BSA were injected. (C) C38-2 IgE–sensitized mice were pretreated with saline, GST, or GST-N19 (N19) before injection with mHRF-His6. (D) LPR in FcεRIα–/– mice. (E) Inhibition of IgE/antigen-induced PCA reactions by GST-N19. WT mice were sensitized overnight with the indicated IgEs. Left ears were injected with GST and right ears were injected with GST-N19, then TNP26-BSA was injected in both ears. Ear thickness was measured. Insets show area under curve (AUC). *P < 0.05, #P < 0.01, §P < 0.001. 3–6 mice were used for each cohort. Data are representative of 2 (A–D) or 3 (E) experiments.