Blood. 2010 Oct 22. [Epub ahead of print]
A novel role for IL-22R1 as a driver of inflammation.
Savan R, McFarland AP, Reynolds DA, Feigenbaum L, Ramakrishnan K, Karwan M, Shirota H, Klinman DM, Dunleavy K, Pittaluga S, Anderson SK, Donnelly RP, Wilson WH, Young HA.
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States;
Abstract
The IL-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but we found that this receptor is expressed on T-cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic (tg) mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement and subsequent lethality due to multi-organ inflammation. The IL-22R1 tg animals developed neutrophilia that correlated with increased levels of circulating IL-17 and G-CSF. In addition, these mice had increased serum IL-22 levels, suggesting that T-cells expressing IL-22R1 generate IL-22 in a positive auto-regulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+) ALCL patients, and detected elevated levels of IL-22, IL-17 and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL. |
