Kiessling Stephan, Muller-Newen Gerhard, Leeb Sandra N, Hausmann Martin, Rath Heiko C, Strater Jorn, Spottl Tanja, Schlottmann Klaus, Grossmann Johannes, Montero-Julian F A, Scholmerich Jurgen, Andus Tilo, Buschauer Armin, Heinrich Peter C, Rogler Gerhard
Department of Internal Medicine I, University of Regensburg, Germany.
J Biol Chem. 2004 Mar 12;279(11):10304-15. doi: 10.1074/jbc.M312757200. Epub 2003 Dec 29.
A tissue-protective effect of interleukin-11 (IL-11) for the intestinal mucosa has been postulated from animal models of inflammatory bowel disease (IBD). Despite the fact that the clinical usefulness of the anti-inflammatory effects of this cytokine is presently investigated in patients with IBD, there are no data available regarding the target cells of IL-11 action and the mechanisms of tissue protection within the human colonic mucosa. IL-11 responsiveness is restricted to cells that express the interleukin-11 receptor alpha-chain (IL-11Ralpha) and an additional signal-transducing subunit (gp130). In this study, we identified the target cells for IL-11 within the human colon with a new IL-11Ralpha monoclonal antibody and investigated the functional expression of the receptor and downstream effects of IL-11-induced signaling. Immunohistochemistry revealed expression of the IL-11Ralpha selectively on colonic epithelial cells. HT-29 and colonic epithelial cells (CEC) constitutively expressed IL-11Ralpha mRNA and protein. Co-expression of the signal-transducing subunit gp130 was also demonstrated. IL-11 induced signaling through triggering activation of the Jak-STAT pathway without inducing anti-inflammatory or proliferative effects in colonic epithelial cells. However, IL-11 stimulation resulted in a dose-dependent tyrosine phosphorylation of Akt, a decreased activation of caspase-9, and a reduced induction of apoptosis in cultured CEC. In HLA-B27 transgenic rats treated with IL-11, a reduction of apoptotic cell numbers was found. This study demonstrates functional expression of the IL-11Ralpha restricted on CEC within the human colonic mucosa. IL-11 induced signaling through triggering activation of the Jak-STAT pathway, without inducing anti-inflammatory or proliferative effects. The beneficial effects of IL-11 therapy are likely to be mediated by CEC via activation of the Akt-survival pathway, mediating antiapoptotic effects to support mucosal integrity.
从炎症性肠病（IBD）动物模型推测白细胞介素-11（IL-11）对肠黏膜具有组织保护作用。尽管目前正在研究这种细胞因子的抗炎作用在IBD患者中的临床实用性，但关于IL-11作用的靶细胞以及人结肠黏膜内组织保护机制的数据尚不可得。IL-11反应性仅限于表达白细胞介素-11受体α链（IL-11Rα）和另一个信号转导亚基（gp130）的细胞。在本研究中，我们用一种新的IL-11Rα单克隆抗体鉴定了人结肠内IL-11的靶细胞，并研究了该受体的功能表达以及IL-11诱导信号的下游效应。免疫组织化学显示IL-11Rα选择性地在结肠上皮细胞上表达。HT-29和结肠上皮细胞（CEC）组成性地表达IL-11Rα mRNA和蛋白。还证实了信号转导亚基gp130的共表达。IL-11通过触发Jak-STAT途径的激活来诱导信号，而在结肠上皮细胞中不诱导抗炎或增殖作用。然而，IL-11刺激导致Akt的剂量依赖性酪氨酸磷酸化、caspase-9的激活降低以及培养的CEC中凋亡诱导减少。在用IL-11治疗的HLA-B27转基因大鼠中，发现凋亡细胞数量减少。本研究证明了IL-11Rα在人结肠黏膜内的CEC上的功能性表达。IL-11通过触发Jak-STAT途径的激活来诱导信号，而不诱导抗炎或增殖作用。IL-11治疗的有益作用可能由CEC通过激活Akt存活途径介导，介导抗凋亡作用以支持黏膜完整性。
