IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression.
Human cytomegalovirus virus (CMV) is a major cause of morbidity and mortality in immunocompromised individuals. Recently, a novel group of cytokines [interleukin (IL)-28A/B and IL-29, also termed interferon (IFN)-lambdas] has been described. Here, we demonstrate that intestinal epithelial cell (IEC) lines as well as murine and human colonic tissue express the IFN-lambda receptor subunits IL-28R and IL-10R2. IL-28A and IL-29 binding to their receptor complex activates ERK-1/2 and stress-activated protein kinase/c-Jun NH2-terminal kinase MAPKs and Akt, resulting in increased IL-8 protein expression. IFN-lambdas also induce phosphorylation of signal transducer and activator of transcription 1 and significantly increase mRNA expression of suppressor of cytokine signaling 3 and the antiviral proteins myxovirus resistance A and 2',5'-oligoadenylate synthetase. These signals result in an up to 83% reduction of cells positive for human CMV immediate-early protein after human CMV infection. In mice, IL-28A mRNA expression is upregulated after infection with murine CMV in vivo. Both IL-28A and IL-29 significantly decrease cell proliferation but have no effect on Fas-induced apoptosis. In conclusion, IECs express functional receptors for IFN-lambdas, which mediate antiviral and antiproliferative signals in IECs, suggesting a potential for therapeutic use in certain viral infections and as (antiproliferative) anticancer therapy.
Brand
Stephan
S
Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, D-81377 Munich, Germany. stephan.brand@med.uni-muenchen.de
Beigel
Florian
F
Olszak
Torsten
T
Zitzmann
Kathrin
K
Eichhorst
Sören T
ST
Otte
Jan-Michel
JM
Diebold
Joachim
J
Diepolder
Helmut
H
Adler
Barbara
B
Auernhammer
Christoph J
CJ
Göke
Burkhard
B
Dambacher
Julia
J
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons; D016209:Interleukin-8 / Q000096:biosynthesis; D007378:Interleukins / Q000378:metabolism*; D007413:Intestinal Mucosa; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D018121:Receptors, Cytokine / Q000378:metabolism; D015398:Signal Transduction; D000095022:Interferon Lambda
D015088:2',5'-Oligoadenylate Synthetase; D016207:Cytokines; D019204:GTP-Binding Proteins; D007372:Interferons; D016209:Interleukin-8; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D064547:Myxovirus Resistance Proteins; D018121:Receptors, Cytokine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C471046:interleukin 28alpha receptor; C475085:OAS1 protein, human