Song G Y, Chung C S, Chaudry I H, Ayala A
Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, 02903, USA.
Surgery. 2000 Aug;128(2):133-8. doi: 10.1067/msy.2000.107282.
Although studies have shown that there is a marked depression in cell-mediated (T(H)(1)) immunity after the onset of sepsis, the mechanism by which this occurs remains unknown. In this regard, the T(H2) cytokine IL-4 is known to regulate T(H1) and T(H2) cell responsiveness primarily through the activation of the signal transducer and activation of transcription factor-6 (Stat6) pathway.
We hypothesized that IL-4 may contribute to the suppression of cell-mediated immunity and to death seen in sepsis and that IL-4 may be acting through the Stat6 pathway. To determine this, we induced cecal ligation and puncture (CLP) or sham-CLP in male BALB/c mice. Mice received 2 mg of monoclonal antibody against IL-4 or IgG control at 12 hours after CLP (ie, at the onset of immune suppression). Splenic T cells were then isolated 24 hours after CLP and stimulated with monoclonal antibody to CD3. Cytokine release and Stat6 phosphorylation (activation) were determined. In a separate group of animals, survival was assessed over 10 days.
The results indicate that after CLP, T cells are suppressed in their ability to release the T(H1) cytokines, IL-2 and IFN-gamma. Alternatively, the release of T(H2) cytokines IL-10 and IL-4 is markedly increased after CLP. This was associated with an increase in phosphorylated Stat6 protein. In vivo treatment of mice with monoclonal antibody to IL-4 at 12 hours after CLP restores T(H1) responsiveness while preventing the increase in T(H2) cytokine release and Stat6 phosphorylation. Furthermore, neutralization of IL-4 markedly increased the survival rates in septic animals.
Taken together, these data indicate that the T(H2) cytokine IL-4 contributes to the suppression of cell-mediated immunity and death associated with polymicrobial sepsis and suggest that IL-4 may be acting through the Stat6 pathway in septic animals.
尽管研究表明脓毒症发作后细胞介导的（辅助性T细胞1型，Th1）免疫存在显著抑制，但其发生机制仍不清楚。在这方面，已知辅助性T细胞2型（Th2）细胞因子白细胞介素-4（IL-4）主要通过激活信号转导子和转录激活因子6（Stat6）途径来调节Th1和Th2细胞反应性。
我们假设IL-4可能导致脓毒症中细胞介导免疫的抑制和死亡，并且IL-4可能通过Stat6途径发挥作用。为了确定这一点，我们在雄性BALB/c小鼠中诱导盲肠结扎和穿刺（CLP）或假手术CLP。小鼠在CLP后12小时（即免疫抑制开始时）接受2毫克抗IL-4单克隆抗体或IgG对照。然后在CLP后24小时分离脾T细胞，并用抗CD3单克隆抗体刺激。测定细胞因子释放和Stat6磷酸化（激活）情况。在另一组动物中，评估10天内的存活率。
结果表明，CLP后，T细胞释放Th1细胞因子白细胞介素-2（IL-2）和干扰素-γ（IFN-γ）的能力受到抑制。另外，CLP后Th2细胞因子白细胞介素-10（IL-10）和IL-4的释放显著增加。这与磷酸化Stat6蛋白的增加有关。CLP后12小时用抗IL-4单克隆抗体对小鼠进行体内治疗可恢复Th1反应性，同时防止Th2细胞因子释放和Stat6磷酸化增加。此外，中和IL-4显著提高了脓毒症动物的存活率。
综上所述，这些数据表明Th2细胞因子IL-4导致与多微生物脓毒症相关的细胞介导免疫抑制和死亡，并提示IL-4可能在脓毒症动物中通过Stat6途径发挥作用。
