Journal of Clinical Medicine, 2019. 8(9), 1350-1367, DOI: https://doi.org/10.3390/jcm8091350

TSLP Exacerbates Septic Inflammation via Murine Double Minute 2(MDM2) Signaling Pathway

Na-Ra Han, Phil-Dong Moon;Hyung-Min Kim;Hyun-Ja Jeong

Abstract

Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is aserious systemic inflammatory reaction with organ dysfunction by infection. However, the function ofTSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism ofTSLP during sepsis. Sepsis was induced by lipopolysaccharides (LPS) or Escherichia coli DH5 injectionin mice. TSLP levels were measured in human subjects, mice, and macrophages. TSLP deficiency ormurine double minute 2 (MDM2) deficiency was induced using siRNA or anMDM2inhibitor, nutlin-3a.We found that TSLP levels were elevated in serum of patients and mice with sepsis. TSLP deficiencylowered liver damage and inflammatory cytokine levels in mice with sepsis. TSLP was producedby the MDM2/NF- B signaling pathway in LPS-stimulated macrophages. TSLP downregulationby an MDM2 inhibitor, nutlin-3a, alleviated clinical symptoms and septic inflammatory responses.Pharmacological inhibition of TSLP level by cisplatin reduced the septic inflammatory responses.Altogether, the present results show that TSLP exacerbates septic inflammation via the MDM2signaling pathway, suggesting that TSLP may be a potential target for the treatment of sepsis.

• DOI: https://doi.org/10.3390/jcm8091350
• ISBN or ISSN: 2077-0383

• 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
• This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.