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

J Biol Chem. 2002 Sep 13;277(37):33676-82. doi: 10.1074/jbc.M204204200. Epub 2002 Jun 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / enzymology
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Interleukin-10 / pharmacology*
  • Interleukin-22
  • Interleukins / pharmacology*
  • JNK Mitogen-Activated Protein Kinases
  • Janus Kinase 2
  • Milk Proteins*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins*
  • Rats
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Signal Transduction / drug effects
  • TYK2 Kinase
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • Interleukins
  • Milk Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat1 protein, rat
  • Stat3 protein, rat
  • Trans-Activators
  • Interleukin-10
  • Protein-Tyrosine Kinases
  • Jak2 protein, rat
  • Janus Kinase 2
  • TYK2 Kinase
  • Tyk2 protein, rat
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases