Interleukin‐6 promotes skeletal muscle catabolism by activating tryptophan–indoleamine 2,3‐dioxygenase 1–kynurenine pathway during intra‐abdominal sepsis

作者：Tingbin Xie, Tengfei Lv, Tenghui Zhang, Dengyu Feng, Feng Zhu, Yi Xu, Liang Zhang, Lili Gu, Zhen Guo, Chao Ding, Jianfeng Gong · 发表于：Journal of Cachexia Sarcopenia and Muscle · 年份：2023 · DOI：10.1002/jcsm.13193 · 被引用次数：28 · 研究领域：Exercise and Physiological Responses、Intensive Care Unit Cognitive Disorders、Tryptophan and brain disorders

Abstract Background Inflammatory cytokine interleukin‐6 (IL‐6) plays a pivotal role in skeletal muscle degradation after intra‐abdominal sepsis (IAS), with mechanism remained to be elucidated. Indoleamine 2,3‐dioxygenase 1 (IDO‐1), a key enzyme in converting tryptophan into kynurenine, could be activated by IL‐6, and kynurenine has been shown to be involved in muscle degradation. We hypothesized that IL‐6 could promote muscle degradation via tryptophan–IDO‐1–kynurenine pathway in IAS patients. Methods Serum and rectus abdominis (RA) were obtained from IAS or non‐IAS patients. Mouse model of IAS‐induced muscle wasting was generated by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection. IL‐6 signalling was blocked by anti‐mouse IL‐6 antibody (IL‐6‐AB), and the IDO‐1 pathway was blocked by navoximod. To elucidate the role of kynurenine in muscle mass and physiology, kynurenine was administered to IAS mice treated with IL‐6‐AB. Results Compared to non‐IAS patients, kynurenine levels in serum (+2.30‐fold vs. non‐IAS, P < 0.001) and RA (+3.11‐fold vs. non‐IAS, P < 0.001) were elevated, whereas tryptophan levels in serum (−53.65% vs. non‐IAS, P < 0.01) and RA (−61.39% vs. non‐IAS, P < 0.01) were decreased. Serum IL‐6 level of the IAS group was significantly higher compared to non‐IAS patients (+5.82‐fold vs. non‐IAS, P = 0.01), and muscle cross‐sectional area (MCSA) was markedly reduced compared to non‐IAS patients (−27.73% vs. non‐IAS, P < 0.01...