title: Human airway eosinophils exhibit preferential reduction in STAT signaling capacity and increased CISH expression.
abstract: Allergic asthma, a chronic respiratory disorder marked by inflammation and recurrent airflow obstruction, is associated with elevated levels of IL-5 family cytokines and elevated numbers of eosinophils (EOS). IL-5 family cytokines elongate peripheral blood EOS (EOS(PB)) viability, recruit EOS(PB) to the airways, and, at higher concentrations, induce degranulation and reactive oxygen species generation. Although airway EOS (EOS(A)) remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOS(A) with IL-5 family cytokines no longer confers a survival advantage. Because the IL-5 family receptors have common signaling capacity, but are uncoupled from EOS(A) survival, whereas other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOS(A) possess a JAK/STAT-specific regulatory mechanism (because JAK/STAT signaling is critical to EOS survival). We found that IL-5 family-induced STAT3 and STAT5 phosphorylation is attenuated in EOS(A) relative to blood EOS from airway allergen-challenged donors. However, IL-5 family-induced ERK1/2 phosphorylation is not altered between EOS(A) and EOS from airway allergen-challenged donors. These observations suggest EOS(A) possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOS(PB), IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOS(A) express significantly more CISH and SOCS1 mRNA and CISH protein than EOS(PB) counterparts. In EOS(PB), long-term pretreatment with IL-5 family cytokines, to varying degrees, attenuates IL-5 family-induced STAT5 phosphorylation. These data support a model in which IL-5 family cytokines trigger a selective downregulation mechanism in EOS(A) for JAK/STAT pathways.
authors: Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
authors: Mandy E
authors: ME
authors: Burnham
authors: Cynthia J
authors: CJ
authors: Koziol-White
authors: Stephane
authors: S
authors: Esnault
authors: Mary E
authors: ME
authors: Bates
authors: Michael D
authors: MD
authors: Evans
authors: Paul J
authors: PJ
authors: Bertics
authors: Loren C
authors: LC
authors: Denlinger
mesh_terms: D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D015848:Interleukin-5; D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; C508599:IL5 protein, human
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