title: IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression.
abstract: 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.
authors.affiliation: Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, D-81377 Munich, Germany. stephan.brand@med.uni-muenchen.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Sören T
authors.initials: ST
authors.lastname: Eichhorst
authors.forename: Jan-Michel
authors.initials: JM
authors.lastname: Otte
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Helmut
authors.initials: H
authors.lastname: Diepolder
authors.forename: Barbara
authors.initials: B
authors.lastname: Adler
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Julia
authors.initials: J
authors.lastname: Dambacher
mesh_terms: 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
chemical_list: 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