Bates

Bruijnzeel

Cynthia J. Koziol-White

DiPersio

Loren C. Denlinger

López

Mandy E. Burnham

Mary E. Bates

Michael D. Evans

Monahan

Paul J. Bertics

Schweizer

Sedgwick

Stephane Esnault

Yukawa

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 (EOSPB) viability, recruit EOSPB to the airways, and, at higher concentrations, induce degranulation and reactive oxygen species generation. Although airway EOS (EOSA) remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOSA 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 EOSA survival, whereas other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOSA 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 EOSA relative to blood EOS from airway allergen–challenged donors. However, IL-5 family–induced ERK1/2 phosphorylation is not altered between EOSA and EOS from airway allergen–challenged donors. These observations suggest EOSA possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOSPB, IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOSA express significantly more CISH and SOCS1 mRNA and CISH protein than EOSPB counterparts. In EOSPB, 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 EOSA for JAK/STAT pathways.</jats:p

Crossref

The Journal of Immunology

Human Airway Eosinophils Exhibit Preferential Reduction in STAT Signaling Capacity and Increased CISH Expression

Human Airway Eosinophils Exhibit Preferential Reduction in STAT Signaling Capacity and Increased CISH Expression

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