Dusp5 negatively regulates IL-33-mediated eosinophil survival and function.
Mitogen-activated protein kinase (MAPK) activation controls diverse cellular functions including cellular survival, proliferation, and apoptosis. Tuning of MAPK activation is counter-regulated by a family of dual-specificity phosphatases (DUSPs). IL-33 is a recently described cytokine that initiates Th2 immune responses through binding to a heterodimeric IL-33Rα (ST2L)/IL-1α accessory protein (IL-1RAcP) receptor that coordinates activation of ERK and NF-κB pathways. We demonstrate here that DUSP5 is expressed in eosinophils, is upregulated following IL-33 stimulation and regulates IL-33 signaling. Dusp5(-/-) mice have prolonged eosinophil survival and enhanced eosinophil effector functions following infection with the helminth Nippostrongylus brasiliensis. IL-33-activated Dusp5(-/-) eosinophils exhibit increased cellular ERK1/2 activation and BCL-XL expression that results in enhanced eosinophil survival. In addition, Dusp5(-/-) eosinophils demonstrate enhanced IL-33-mediated activation and effector functions. Together, these data support a role for DUSP5 as a novel negative regulator of IL-33-dependent eosinophil function and survival.
Department of Immunology, Genentech, Inc., South San Francisco, CA, USA.
Derek A
DA
Holmes
Department of Immunology, Genentech, Inc., South San Francisco, CA, USA.
Jung-Hua
JH
Yeh
Department of Translational Immunology, Genentech, Inc., South San Francisco, CA, USA.
Donghong
D
Yan
Department of Translational Immunology, Genentech, Inc., South San Francisco, CA, USA.
Min
M
Xu
Department of Immunology, Genentech, Inc., South San Francisco, CA, USA acc@gene.com.
Andrew C
AC
Chan
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D054637:Dual-Specificity Phosphatases / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D005260:Female; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017206:Strongylida Infections / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000469:parasitology
D004268:DNA-Binding Proteins; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D054637:Dual-Specificity Phosphatases; C546197:Dusp5 protein, mouse
BCL‐XL; dual‐specificity phosphatase 5; eosinophil survival