Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells.
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.
Kiessling
Stephan
S
Department of Internal Medicine I, University of Regensburg, Germany.
Muller-Newen
Gerhard
G
Leeb
Sandra N
SN
Hausmann
Martin
M
Rath
Heiko C
HC
Strater
Jorn
J
Spottl
Tanja
T
Schlottmann
Klaus
K
Grossmann
Johannes
J
Montero-Julian
F A
FA
Scholmerich
Jurgen
J
Andus
Tilo
T
Buschauer
Armin
A
Heinrich
Peter C
PC
Rogler
Gerhard
G
D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000378:metabolism; D053703:Interleukin-11 Receptor alpha Subunit; D016209:Interleukin-8 / Q000378:metabolism; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism; D009092:Mucous Membrane / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000737:chemistry*; D053702:Receptors, Interleukin-11; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C508428:IL11RA protein, human; C494199:IL6ST protein, human; C508430:Il11ra1 protein, rat; C494201:Il6st protein, rat; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases