An anti-inflammatory cytokine, Interleukin-11 : A therapeutic target against septic MODS

脓毒症中过度的全身炎症反应会导致严重的组织损伤，导致包括肝脏在内的多器官衰竭，肝脏是脓毒症的靶器官，也是炎症介质的来源。白细胞介素-11 （Interleukin-11, IL-11）是一种多效性细胞因子，可通过下调多种促炎介质来抑制炎症。虽然有报道称重组人IL-11 （rhIL-11）可能对脓毒症的治疗有用，但IL-11对脓毒症相关肝损伤的影响尚未得到评估。在本研究中，我们在脓毒症大鼠模型中检测了rhIL-11特异性对肝损伤的影响。雄性Sprague-Dawley大鼠腹腔注射细菌脂多糖（LPS,20 mg/kg）。部分大鼠在注射LPS后立即给予rhIL-11 （150μg/kg, ig）。LPS处理引起严重肝损伤，血清谷丙转氨酶（ALT）和天冬氨酸转氨酶（AST）活性显著升高，肝细胞广泛坏死，肿瘤坏死因子-α (TNF-α) mRNA、诱导型一氧化氮合酶（iNOS） mRNA和核因子-κB (NF-κB) DNA结合活性显著升高。相比之下，rhIL-11处理显著抑制lps诱导的肝损伤，从所有这些指标的改善来判断。此外，rhIL-11治疗显著降低lps诱导的死亡率。这些结果表明，rhIL-11具有有效的抗炎活性，在lps诱导的脓毒症中起保护作用。此外，rhIL-11可能成为脓毒症的新药物靶点。

Excessive systemic inflammatory responses in sepsis cause severe tissue injuries leading to multiple organ failures including that of liver, the target organ as well as a source of inflammatory mediators in sepsis. Interleukin-11 (IL-11) is a pleiotropic cytokine that can suppress inflammation through the down-regulation of multiple pro-inflammatory mediators. Although it has been reported that recombinant human IL-11 (rhIL-11) may be useful in the treatment of sepsis, the effect of IL-11 on hepatic injury associated with sepsis has not been evaluated. In the present study, we examined the effect of rhIL-11 specifically on hepatic injury in a rat model of sepsis. Male Sprague-Dawley rats were injected intraperitoneally (i.p.) with bacterial lipopolysaccharide (LPS,20 mg/kg). Immediately after LPS injection, some rats were also treated with rhIL-11 (150μg/kg, i.p.). LPS treatment induced severe hepatic injury as revealed by marked increases in serum alanine transaminase (ALT) and aspartate transaminase (AST) activities, extensive hepatocyte necrosis, tumor necrosis factor-α (TNF-α) mRNA, inducible nitric oxide synthase (iNOS) mRNA, and DNA binding activity of nuclear factor-κB (NF-κB). In contrast, rhIL-11 treatment significantly suppressed the LPS-induced hepatic injury, as judged by amelioration of all these indices. In addition, rhIL-11 treatment markedly decreased LPS-induced mortality. These results indicate that rhIL-11 possesses a potent anti-inflammatory activity that plays a protective role in the LPS-induced sepsis. Moreover, rhIL-11 may be a new drug target for sepsis.