TY - JOUR
T1 - dTBP2 attenuates severe airway inflammation by blocking inflammatory cellular network mediated by dTCTP
AU - Cho, Hyunsoo
AU - Kim, Hyo Kyeong
AU - Oh, Areum
AU - Jeong, Mi Gyeong
AU - Song, Jiseo
AU - Lee, Kyunglim
AU - Hwang, Eun Sook
N1 - Funding Information:
We thank Ms Yu Jeong Choi and Hwa Young Kim for their help with cell culture and mouse handling. This work was supported by the grants of the National Research Foundation ( NRF-2018R1A5A2025286 , and 2020R1A2C2004679 for ESH; NRF-2020M3E5E2036808 and 2021R1A2C2003629 for KL) funded by the Ministry of Education, Science, and Technology .
Publisher Copyright:
© 2021 The Authors
PY - 2021/12
Y1 - 2021/12
N2 - Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms. In this study, we explored the dTCTP-mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma. LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion. These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.
AB - Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms. In this study, we explored the dTCTP-mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma. LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion. These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.
KW - Airway epithelial cell
KW - Cellular network
KW - Mast cell
KW - dTBP2
KW - dTCTP
UR - http://www.scopus.com/inward/record.url?scp=85116516857&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2021.112316
DO - 10.1016/j.biopha.2021.112316
M3 - Article
C2 - 34628164
AN - SCOPUS:85116516857
VL - 144
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
SN - 0753-3322
M1 - 112316
ER -