A soluble form of IL-27Rα is a natural IL-27 antagonist.
IL-27 is a cytokine of the IL-12 family that plays a key role in the regulation of inflammatory and T cell responses. Its receptor is composed of IL-27Rα and gp130 and activates the STAT pathway. We show in this study, using an ELISA that we developed, that a naturally occurring soluble form of IL-27Rα (sIL-27Rα) is produced by human activated CD4(+) and CD8(+) T cells, B cells, myeloid cells, and various cell lines. sIL-27Rα is present at a mean concentration of 10,344 ± 1,274 pg/ml in the sera from healthy individuals. Biochemical studies showed that sIL-27Rα is released as two N-glycosylated variants of ∼ 90 and ∼ 70 kDa. In IL-27Rα-transfected COS7 cells, primary cells, and cell lines, production of sIL-27Rα is inhibited by the metalloprotease inhibitors GM6001 and TAPI-0. Importantly, natural sIL-27Rα binds rIL-27, inhibits IL-27 binding to its cell surface receptor, and is a potent inhibitor of IL-27 signaling, as shown by its ability to specifically block IL-27-mediated STAT activation, at low molar excess over IL-27. Also, we found that serum levels of sIL-27Rα were elevated in patients with Crohn's disease, a Th1-mediated disease. These findings suggest that sIL-27Rα may play important immunoregulatory functions under normal and pathological conditions.
Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75 015 Paris, France; Institut Necker Enfants Malades, INSERM U1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75 015 Paris, France;
Céline
C
Dietrich
Institut Necker Enfants Malades, INSERM U1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75 015 Paris, France; INSERM U1013, Université Paris Descartes, Sorbonne Paris Cité, 75 015 Paris, France; and.
Sophie
S
Candon
Service de Gastroentérologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75 015 Paris, France.
Frank M
FM
Ruemmele
Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75 015 Paris, France; Institut Necker Enfants Malades, INSERM U1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75 015 Paris, France; odile.devergne@inserm.fr.
Odile
O
Devergne
D000328:Adult; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D008297:Male; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
C112441:IL27RA protein, human; D007378:Interleukins; C464565:MYDGF protein, human; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors