Abstract
Dimerized translationally controlled tumor protein (dTCTP) amplifies allergic responses through activation of several types of immune cells and release of inflammatory mediators. In particular, dTCTP plays an important role in histamine release by triggering mast cells and has been proposed as a target in the treatment of allergic diseases. dTCTP-binding peptide 2 (dTBP2) is known to attenuate severe allergic rhinitis and asthma through inhibition of dTCTP activity on airway epithelial cells and T cells; however, it is unclear whether dTBP2 affects mast cell function and mast cell disease. In this study, we explored the effects of dTBP2 on mast cell degranulation and allergen-induced anaphylactic reactions. We found that bacterial product lipopolysaccharide increased the expression of dTCTP in mast cells and rapidly released dTCTP by the mast cell stimulator compound 48/80. Interestingly, the released dTCTP further promoted mast cell degranulation in an autocrine activation manner and increased calcium mobilization in mast cells, which is essential for degranulation. Furthermore, dTBP2 directly and dose-dependently inhibited in vitro mast cell degranulation enhanced by compound 48/80, suggesting a direct and potent anti-anaphylactic activity of dTBP2. dTBP2 also significantly suppressed the dTCTP-induced degranulation and histamine release through inhibition of the p38 MAPK signaling pathway and suppression of lysosomal expansion and calcium mobilization in mast cells. More importantly, in vivo administration of dTBP2 decreased mortality and significantly attenuated histamine release and inflammatory cytokine production in compound 48/80-induced systemic anaphylactic reactions. These results suggest that dTBP2 is beneficial for the control of anaphylaxis with increased dTCTP.
Highlights
Anaphylaxis is a severe and potentially life-threatening allergic response and occurs rapidly after exposure to provoking agents (Bochner and Lichtenstein, 1991)
Since dTCTP-binding peptide 2 (dTBP2) has been identified as a specific inhibitor for dTCTP, which is primarily produced by mononuclear cells and released under allergic conditions, we first asked whether mast cells produce dTCTP and dTCTP modulates mast cell function
Time-course analysis of dTCTP secretion by compound 48/80 (C48/80) treatment demonstrated a rapid release of dTCTP within 5 min after C48/80 treatment and persistent release of dTCTP during mast cell degranulation induced by C48/80 (Figure 1D)
Summary
Anaphylaxis is a severe and potentially life-threatening allergic response and occurs rapidly after exposure to provoking agents (Bochner and Lichtenstein, 1991). Activation of potential effector cells, mainly mast cells, immediately releases mediators such as histamine and various proteases and pro-inflammatory cytokines and subsequently promotes recruitment of type 2 T helper cells, activation of dendritic cells and airway epithelial cells, thereby exacerbating allergic disorders (Kraft and Kinet, 2007; Galli and Tsai, 2012). A better understanding of the mechanisms and causes of anaphylaxis will help develop therapeutics based on precision medicine. Anaphylaxis is caused by IgE-mediated mast cell degranulation and IgE-independent mechanisms such as IgGdependent anaphylaxis, complement-mediated anaphylaxis, and drug-induced anaphylaxis (Finkelman et al, 2016). Since compound 48/80 (C48/80) induces mast cell activation and degranulation, it is widely used as a potent histamine liberator in animal and tissue models of systemic anaphylaxis (Paton, 1951; Wang et al, 2020)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
