TY - JOUR
T1 - Tollip interaction with STAT3
T2 - a novel mechanism to regulate human airway epithelial responses to type 2 cytokines
AU - Schaunaman, Niccolette
AU - Dimasuay, Kris Genelyn
AU - Kraft, Monica
AU - Chu, Hong Wei
N1 - Funding Information:
This work was supported by the NIH Grant: U19AI125357. This funding source was not involved in the preparation of data or the manuscript.
Funding Information:
M.K. has received grants from Sanofi, ALA, Chiesi, and AstraZeneca; royalties from Elsevier; and consulting fees from AstraZeneca and Sanofi outside the submitted work. The rest of the authors declare that they have no competing interests.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Background: Toll-interacting protein (Tollip) is one of the key negative regulators in host innate immunity. Genetic variation of Tollip has been associated with less Tollip expression and poor lung function in asthmatic patients, but little is known about the role of Tollip in human airway type 2 inflammatory response, a prominent feature in allergic asthma. Objective: Our goal was to determine the role and underlying mechanisms of Tollip in human airway epithelial responses such as eotaxin to type 2 cytokine IL-13. Methods: Tollip deficient primary human airway epithelial cells from 4 healthy donors were generated by the gene knockdown approach and stimulated with IL-13 to measure activation of transcription factor STAT3, and eotaxin-3, an eosinophilic chemokine. Results: Following IL-13 treatment, Tollip deficient cells had significantly higher levels of STAT3 activation and eotaxin-3 than the scrambled control counterpart, which was reduced by a STAT3 inhibitor. Interaction between Tollip and STAT3 proteins was identified by co-immunoprecipitation. Conclusion: Our results, for the first time, suggest that Tollip inhibits excessive eotaxin-3 induction by IL-13, in part through the interaction and inhibition of STAT3. These findings lend evidence to the potential of a STAT3 inhibitor as a therapeutic target, especially for type 2 inflammation-high asthmatics with Tollip deficiency.
AB - Background: Toll-interacting protein (Tollip) is one of the key negative regulators in host innate immunity. Genetic variation of Tollip has been associated with less Tollip expression and poor lung function in asthmatic patients, but little is known about the role of Tollip in human airway type 2 inflammatory response, a prominent feature in allergic asthma. Objective: Our goal was to determine the role and underlying mechanisms of Tollip in human airway epithelial responses such as eotaxin to type 2 cytokine IL-13. Methods: Tollip deficient primary human airway epithelial cells from 4 healthy donors were generated by the gene knockdown approach and stimulated with IL-13 to measure activation of transcription factor STAT3, and eotaxin-3, an eosinophilic chemokine. Results: Following IL-13 treatment, Tollip deficient cells had significantly higher levels of STAT3 activation and eotaxin-3 than the scrambled control counterpart, which was reduced by a STAT3 inhibitor. Interaction between Tollip and STAT3 proteins was identified by co-immunoprecipitation. Conclusion: Our results, for the first time, suggest that Tollip inhibits excessive eotaxin-3 induction by IL-13, in part through the interaction and inhibition of STAT3. These findings lend evidence to the potential of a STAT3 inhibitor as a therapeutic target, especially for type 2 inflammation-high asthmatics with Tollip deficiency.
KW - Airway epithelial cells
KW - IL-13
KW - Protein–protein interaction
KW - STAT3
KW - Tollip
KW - Type 2 inflammation
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U2 - 10.1186/s12931-022-01941-x
DO - 10.1186/s12931-022-01941-x
M3 - Letter
C2 - 35172835
AN - SCOPUS:85124775173
VL - 23
JO - Respiratory Research
JF - Respiratory Research
SN - 1465-9921
IS - 1
M1 - 31
ER -