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IL-22 signaling complexity
Dysregulated signaling by the cytokine interleukin-22 (IL-22) results in inflammatory disease, and inhibitors of IL-22 are in clinical trials for the treatment of psoriasis and rheumatoid arthritis. However, IL-22 already has natural inhibitors in the form of IL-22 binding proteins (IL-22BPs), which are soluble, receptor-like proteins that bind to IL-22 and prevent it from binding its receptors on target cells. Lim et al. characterized the three IL-22BP isoforms of humans. One isoform was not secreted and so failed to antagonize IL-22 signaling. Compared with IL-22BPi3, IL-22BPi2 was more potent when tested in binding assays but less abundant in undamaged and noninfected tissues. However, IL-22BPi2 was the only isoform that was increased in abundance in response to inflammatory stimuli. Together, these data suggest that IL-22BPi3 and IL-22BPi2 serve as constitutive and inducible limiters, respectively, of inflammatory signaling mediated by IL-22. Aberrant regulation of this IL-22BP rheostat could contribute to inflammatory disease or prevent appropriate responses to injury or infection in target tissues.
Abstract
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.
