Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10.
IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
Lejeune
Diane
D
Ludwig Institute for Cancer Research, Brussels Branch, Experimental Medicine Unit, Université de Louvain, avenue Hippocrate 74, B-1200 Brussels, Belgium.
Dumoutier
Laure
L
Constantinescu
Stefan
S
Kruijer
Wiebe
W
Schuringa
Jan Jacob
JJ
Renauld
Jean-Christophe
JC
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016753:Interleukin-10 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D053614:Janus Kinase 2; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000097043:Interleukin-22
D004268:DNA-Binding Proteins; D016753:Interleukin-10; D007378:Interleukins; D048031:JNK Mitogen-Activated Protein Kinases; D053614:Janus Kinase 2; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D053634:TYK2 Kinase; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000097043:Interleukin-22; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C507927:Jak2 protein, rat; C499357:Tyk2 protein, rat