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Mol Immunol. 2019 May;109:71-80. doi: 10.1016/j.molimm.2019.03.002. Epub 2019 Mar 11.

The inhibitor of interleukin-3 receptor protects against sepsis in a rat model of cecal ligation and puncture.

Author information

1
Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China; Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
2
Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
3
Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
4
Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
5
Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
6
Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: yangzhengfei@vip.163.com.
7
Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: wanchun.tang@vcuhealth.org.

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. There are multiple cytokines involved in the process of sepsis. As an important upstream cytokine in inflammation, Interleukin-3 (IL-3) plays a crucial role during sepsis, however, its exact role is unclear. The purpose of this study is to discuss the role of IL-3 and its receptor in cecal ligation and puncture (CLP)-induced sepsis in a rat model. The Cluster of Differentiation 123 (CD123, IL-3 receptor alpha chain, IL-3Rac) antibody (anti-CD123) was used to directly target IL-3's receptor and alleviate the effect of IL-3 in the CLP + anti-CD123 group during the early stage of sepsis. CLP was performed in the CLP and CLP + anti-CD123 groups. The time points of observation included 12 h, 24 h, and 5d after the operation. The results showed that the rats in the CLP + anti-CD123 group had lower levels of lactate, serum tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6), and also exhibited a higher core temperature, mean arterial pressure (MAP), Oxygenation Index (PO2/FiO2), and end-tidal carbon dioxide (ETCO2) and serum Interleukin-10 (IL-10) levels after CLP than those in the CLP group. Additionally, administration of anti-CD123 led to a stable down-regulation of tyrosine phosphorylation of the IL-3 receptor, a decline in phosphorylation of the Janus kinase 2 (JAK2) protein, and the signal transduction and activation of transcription 5 (STAT5) proteins in lung tissues. Meanwhile, the study revealed that treatment of anti-CD123 can markedly attenuate histological damages in lung and kidney tissues, improve sublingual microcirculation, and prolong survival post sepsis. In conclusion, anti-CD123 reduces mortality and alleviates organ dysfunction by restraining the JAK2-STAT5 signaling pathway and reduces serum cytokines in the development of early sepsis in a rat model induced by CLP.

KEYWORDS:

Cecal ligation and puncture (CLP); IL-3; Sepsis

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