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http://purl.uniprot.org/citations/28580587http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/28580587http://www.w3.org/2000/01/rdf-schema#comment"

Background

Specific JAK/STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO-1, a stress-inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear.

Methods

We employed Th17-skewing differentiation and NEA mouse models to study the role of HO-1 in regulating IL-6-STAT3-RORγt/SOCS3 signaling pathway to control Th17 cell-mediated neutrophilic airway inflammation. The levels of cytokines and expressions of relative signaling molecules were measured by ELISA, western blot, and qPCR, respectively. Frequency of CD4+ IL-17A+ , CD4+ IL-6R+ , and CD4+ IL-23R+ cells was analyzed by FCM. The interaction between HO-1 and signaling pathway-related proteins was determined by co-immunoprecipitation and western blot.

Results

Here, we show that hemin-induced HO-1 overexpression is required to mediate this process. Specifically, HO-1 decreased STAT3 phosphorylation but not IL-6R/IL-23R expression or JAK1/JAK2 activation in CD4+ T cells. The effect was accompanied by co-inhibition of SOCS3, a negative feedback factor of STAT3 activation. HO-1 bound to three domains on STAT3 (DNA-binding, linker, and transactivation domains) to directly regulate STAT3 activation. Conversely, either forced expression of a constitutively active STAT3 mutant or application of small-interfering RNA (siRNA) for HO-1 reversed these effects.

Conclusions

Our data suggest that HO-1 exerts its inhibitory effect on Th17 cell differentiation by directly associating and blocking STAT3 phosphorylation. We speculate that hemin may be a potential therapeutic candidate for the treatment of other types of immune and pulmonary inflammatory-related diseases."xsd:string
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http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Zhang Y.J."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Zhou T."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Liu J.L."xsd:string
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http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Lin X.L."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Lv J.J."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Xia Z.W."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/author"Di C.X."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/date"2017"xsd:gYear
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/name"Allergy"xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/pages"1972-1987"xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/title"Heme oxygenase-1 directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation."xsd:string
http://purl.uniprot.org/citations/28580587http://purl.uniprot.org/core/volume"72"xsd:string
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