Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling.
The cytokine interleukin-22 (IL-22), which is a member of the IL-10 family, is produced exclusively by immune cells and activates signal transducer and activator of transcription 3 (STAT3) in nonimmune cells, such as hepatocytes, keratinocytes, and colonic epithelial cells, to drive various processes central to tissue homeostasis and immunosurveillance. Dysregulation of IL-22 signaling causes inflammatory diseases. IL-22 binding protein (IL-22BP; encoded by IL22RA2) is a soluble IL-22 receptor, which antagonizes IL-22 activity and has genetic associations with autoimmune diseases. Humans have three IL-22BP isoforms, IL-22BPi1 to IL-22BPi3, which are generated by alternative splicing; mice only have an IL-22BPi2 homolog. We showed that, although IL-22BPi3 had less inhibitory activity than IL-22BPi2, IL-22BPi3 was more abundant in various human tissues under homeostatic conditions. IL-22BPi2 was more effective than IL-22BPi3 at blocking the contribution of IL-22 to cooperative gene induction with the inflammatory cytokine IL-17, which is often present with IL-22 in autoimmune settings. In addition, we found that IL-22BPi1 was not secreted and therefore failed to antagonize IL-22 signaling. Furthermore, IL-22BPi2 was the only isoform that was increased in abundance when myeloid cells were activated by Toll-like receptor 2 signaling or retinoic acid, a maturation factor for myeloid cells. These data suggest that the human IL-22BP isoforms have distinct spatial and temporal roles and coordinately fine-tune IL-22-dependent STAT3 responses in tissues as a type of rheostat.
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
Chrissie
C
Lim
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
MeeAe
M
Hong
Department of Immunology, University of Washington, Seattle, WA 98109, USA. savanram@uw.edu.
Ram
R
Savan
D017398:Alternative Splicing / Q000276:immunology*; D018938:Caco-2 Cells; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008297:Male; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D000097043:Interleukin-22
D020381:Interleukin-17; D007378:Interleukins; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D051195:Toll-Like Receptor 2; D000097043:Interleukin-22; C433253:IL22RA2 protein, human; C515934:Il17a protein, rat; C494086:STAT3 protein, human; C495342:TLR2 protein, human