title: Th2 Cytokines Augment IL-31/IL-31RA Interactions via STAT6-dependent IL-31RA Expression.
abstract: Interleukin 31 receptor α (IL-31RA) is a novel Type I cytokine receptor that pairs with oncostatin M receptor to mediate IL-31 signaling. Binding of IL-31 to its receptor results in the phosphorylation and activation of STATs, MAPK, and JNK signaling pathways. IL-31 plays a pathogenic role in tissue inflammation, particularly in allergic diseases. Recent studies demonstrate IL-31RA expression and signaling in non-hematopoietic cells, but this receptor is poorly studied in immune cells. Macrophages are key immune-effector cells that play a critical role in Th2-cytokine-mediated allergic diseases. Here, we demonstrate that Th2 cytokines IL-4 and IL-13 are capable of up-regulating IL-31RA expression on both peritoneal and bone marrow-derived macrophages from mice. Our data also demonstrate that IL-4Rα-driven IL-31RA expression is STAT6 dependent in macrophages. Notably, the inflammation-associated genes Fizz1 and serum amyloid A (SAA) are significantly up-regulated in M2 macrophages stimulated with IL-31, but not in IL-4 receptor-deficient macrophages. Furthermore, the absence of Type II IL-4 receptor signaling is sufficient to attenuate the expression of IL-31RA in vivo during allergic asthma induced by soluble egg antigen, which may suggest a role for IL-31 signaling in Th2 cytokine-driven inflammation and allergic responses. Our study reveals an important counter-regulatory role between Th2 cytokine and IL-31 signaling involved in allergic diseases.
authors.affiliation: From the Divisions of Pulmonary Medicine and.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edukulla
authors.affiliation: From the Divisions of Pulmonary Medicine and.
authors.forename: Brijendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: From the Divisions of Pulmonary Medicine and.
authors.forename: Vishwaraj
authors.initials: V
authors.lastname: Sontake
authors.affiliation: the ZymoGenetics, Inc. (a Bristol-Myers Squibb Company), Seattle, Washington 98102.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.affiliation: From the Divisions of Pulmonary Medicine and satish.madala@cchmc.org.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018123:Receptors, Interleukin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000472:pathogenicity; D012555:Schistosomiasis mansoni / Q000150:complications / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C488159:Il31ra protein, mouse; D018793:Interleukin-13; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C502588:interleukin-31, mouse; D015847:Interleukin-4
keywords: STAT6; Th2 cytokines; allergic asthma; asthma; cytokine; inflammation; interleukin-31; macrophage; signaling
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