IL-31 receptor (IL-31RA) knockout mice exhibit elevated responsiveness to oncostatin M.
IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. However, recent studies of IL-31RA knockout (KO) mice have suggested that IL-31 signaling may be required to negatively regulate Th2 type responses rather than exacerbate them. Because those studies were performed on genetically modified mice, we examined whether neutralizing IL-31 with a specific mAb would give similar results to IL-31RA KO mice in two Th2 cytokine-associated immune models. We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals. Second, we tested whether the absence of the IL-31RA subunit in IL-31RA KO mice may allow for increased pairing of the OSMR subunit with another cytokine receptor, gp130, resulting in overrepresentation of the heterodimeric receptor for OSM and increased responsiveness to OSM protein. We found that intranasal OSM challenge of IL-31RA KO mice resulted in increased IL-6 and vascular endothelial growth factor production in the lung compared with wild-type littermate control animals. Moreover, PBS-challenged IL-31RA KO mice already had increased levels of vascular endothelial growth factor, which were further increased by OSM challenge. These data imply that IL-31RA-deficient mice produce increased levels of OSM-inducible cytokines during airway sensitization and challenge, which may be the driving force behind the apparent exacerbation of Th2-type inflammatory responses previously observed in these mice.
Department of Immunology, ZymoGenetics Inc., Seattle, WA 98102, USA.
Janine
J
Bilsborough
Sherri
S
Mudri
Eric
E
Chadwick
Brandon
B
Harder
Stacey R
SR
Dillon
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053683:Oncostatin M / Q000276:immunology* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053677:Receptors, Oncostatin M / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; C488159:Il31ra protein, mouse; D018123:Receptors, Interleukin; D053677:Receptors, Oncostatin M; D053683:Oncostatin M