Functional characterisation of the Interleukin-22 receptor
(2003)
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- Authors
- Supervisors
- Renauld, Jean-Christophe
- Abstract
- Interleukin-22 is a cytokine originally identified as an IL-9-induced gene that belongs to a family of IL-10-related cytokines, composed of IL-10, IL-22, IL-19, IL-20, mda-7/IL-24 and AK155/IL-26. So far, the main biological activity of IL-22 is the induction of acute phase reactants expression in liver and pancreas. IL-22 signals through a receptor composed of two chains from the class II cytokine receptor family: IL-22R and IL-10Rb. IL-10Rb is involved in IL-10 signalling, while IL-22R can form a receptor for IL-20 and IL-24 when associated to IL-20Rb. In this work, we analysed the signal transduction pathways activated by IL-22. We found that IL-22, similarly to IL-10, induces activation of JAK1 ant Tyk2, but not JAK2, as well as phosphorylation of STAT1, STAT3 and STAT5 on tyrosine residues. However, we showed that IL-22 specifically activates three distinct MAPK pathways: the MEK-ERK-RSK, the JNK/SAPK and the p38 kinase pathway. IL-22 also induces STAT3 serine phosphorylation, which is not shared by IL-10. This STAT modification is required for maximal transactivation but was only partially affected by MEK1/2 inhibitors, suggesting that other pathways might be involved. By using a chimeric receptor composed of the extracellular part of IL-10Ra and the transmembrane and intracellular parts of IL-22R and by introducing truncations and mutations in this chimera, we could determine the regions of IL-22R required for STAT and MAPK activation. We found that several tyrosine residues of IL-22R can mediate STAT3 tyrosine phosphorylation but that a receptor tyrosine-independent mechanism is also involved. This mechanism is dependent on the C-terminal part of the receptor and seems to require a 180 kDa adaptor. Furthermore, two tyrosines are involved in ERK1/2 phosphorylation and p38 kinase phosphorylation occurs through redundant parts of the receptor. By contrast, IL-22-induced STAT5 phosphorylation is mediated by a single residue of IL-22R. In addition, STAT1 tyrosine phosphorylation is independent on IL-22R tyrosines while STAT3 serine phosphorylation is mediated independently of receptor tyrosine residues by a juxtamembrane domain. This serine phosphorylation does not require STAT3 tyrosine phosphorylation, demonstrating the independency of these two processes. Because IL-22R is also involved in signalling by IL-20 and IL-24, we suggest that these results could be extended to these two other IL-10-related cytokines.
- Affiliations
Citations
Lejeune, D. (2003). Functional characterisation of the Interleukin-22 receptor. https://hdl.handle.net/2078.5/110770