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Am J Respir Cell Mol Biol. 2017 Sep;57(3):346-354. doi: 10.1165/rcmb.2016-0316OC.

IL-4 Induces IL17Rb Gene Transcription in Monocytic Cells with Coordinate Autocrine IL-25 Signaling.

Author information

1 Division of Pulmonary Allergy, and Critical Care, Department of Medicine.
2 Simmons Center for Interstitial Lung Disease, and.
3 Asthma Institute, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
4 Veterans Administration Medical Specialty Line, Pittsburgh VAMC, Pittsburgh, Pennsylvania.


IL-25 and IL-4 signaling in the setting of infection or allergic responses can drive Type 2 inflammation. IL-25 requires the IL-17 receptor B (IL-17Rb) to mediate signaling through nuclear factor κ B (NF-κB) transcriptional activation. Despite the known coexistence of these two cytokines in the Type 2 inflammatory environment, collaborative signaling between the IL-4 and IL-25 axes is poorly explored. Here we demonstrate IL-4 induction of both IL-25 and IL-17Rb protein in human lung tissue culture, primary alveolar macrophages, and the THP-1 monocytic cell line. IL-4 treatment triggers gene transcription for both IL-25 and IL-17Rb but does not alter the receptor mRNA stability. Genetic antagonism of the IL-4 second messenger, signal transducer and activator of transcription 6 (STAT6), with small interfering RNA (siRNA) blunts IL-17Rb mRNA induction by IL-4. IL-25 induces signaling through the canonical NF-κB pathway, and STAT6 or NF-κB signaling inhibitors prevent IL-17Rb expression. Blockade of IL-25 with monoclonal antibody suppresses NF-κB activation after IL-4 treatment, and IL-4-mediated induction of IL-17Rb is suppressed by IL-25 siRNA. IL-25 and IL-17Rb promoter regions harbor putative NF-κB and STAT6 consensus sites, and chromatin immunoprecipitation identified these transcription factors in complex with the IL-17Rb 5' untranslated region. In bronchoalveolar lavage RNA preparations, IL-25 and IL-17Rb mRNA transcripts are increased in asthmatics compared with healthy control subjects, and IL-25 transcript abundance correlates strongly with IL-4 mRNA levels. Thus, these results indicate that IL-4 signaling up-regulates the IL-25 axis in human monocytic cells, and that IL-25 may provide autocrine signals in monocytes and macrophages to sustain IL-17Rb expression and predispose to alternative activation.

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