2. Academic Validation
  3. IL-6 translation is a therapeutic target of human cytokine release syndrome

IL-6 translation is a therapeutic target of human cytokine release syndrome

  • J Exp Med. 2023 Nov 6;220(11):e20230577. doi: 10.1084/jem.20230577.
Yuzhuo Yang # 1 2 3,  Yajing Zhang # 4,  Xiaoyan Xing 1 3,  Gang Xu 5 6,  Xin Lin 1 2 3,  Yao Wang 4,  Meixia Chen 4,  Chunmeng Wang 4,  Bin Zhang 1 3,  Weidong Han 4,  Xiaoyu Hu 1 2 3
Affiliations

Affiliations

  • 1 Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China.
  • 2 Tsinghua-Peking Center for Life Sciences , Beijing, China.
  • 3 Beijing Key Laboratory for Immunological Research on Chronic Diseases , Beijing, China.
  • 4 Department of Bio-Therapeutic, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
  • 5 Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
  • 6 Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China.
  • # Contributed equally.
PMID: 37584653 DOI: 10.1084/jem.20230577
Abstract

Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved β1 Adrenergic Receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.

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