A novel role for IL-22R1 as a driver of inflammation.
The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but 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 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 multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory 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.
Savan
Ram
R
Cancer and Inflammation Program, Center for Cancer Research, Frederick, MD, USA.
McFarland
Adelle P
AP
Reynolds
Della A
DA
Feigenbaum
Lionel
L
Ramakrishnan
Karthika
K
Karwan
Megan
M
Shirota
Hidekazu
H
Klinman
Dennis M
DM
Dunleavy
Kieron
K
Pittaluga
Stefania
S
Anderson
Stephen K
SK
Donnelly
Raymond P
RP
Wilson
Wyndham H
WH
Young
Howard A
HA
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D000097043:Interleukin-22
D000077548:Anaplastic Lymphoma Kinase; D020381:Interleukin-17; D007378:Interleukins; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C415369:interleukin-22 receptor; C000626173:ALK protein, human; C000626174:Alk protein, mouse