Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

Κυριακή 4 Ιουνίου 2017

Heme oxygenase-1 directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation

Abstract

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 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 molecular 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 over-expression 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.

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