Functional Expression of the Interleukin-11 Receptor α-Chain and Evidence of Antiapoptotic Effects in Human Colonic Epithelial Cells

• Published in: The Journal of biological chemistry 2004-03, Vol.279 (11), p.10304-10315
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Antigens, CD - metabolism; Apoptosis; Blotting, Northern; Blotting, Western; Caspase 9; Caspases - metabolism; Cell Division; Cell Line; Cells, Cultured; Colon - cytology; Cytokine Receptor gp130; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells - cytology; Flow Cytometry; Humans; Immunoblotting; Immunohistochemistry; Interleukin-11 - metabolism; Interleukin-11 Receptor alpha Subunit; Interleukin-8 - metabolism; Janus Kinase 1; Membrane Glycoproteins - metabolism; Mucous Membrane - pathology; Phosphorylation; Protein Binding; Protein-Tyrosine Kinases - metabolism; Rats; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - chemistry; Receptors, Interleukin-11; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; STAT3 Transcription Factor; Time Factors; Trans-Activators - metabolism; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M312757200

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 α-chain (IL-11Rα) 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-11Rα monoclonal antibody and investigated the functional expression of the receptor and downstream effects of IL-11-induced signaling. Immunohistochemistry revealed expression of the IL-11Rα selectively on colonic epithelial cells. HT-29 and colonic epithelial cells (CEC) constitutively expressed IL-11Rα 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-11Rα 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.