Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium

Cilia

Martin M Knight²  J Paul Chapple¹  Clare L Thompson¹  Angus KT Wann² 

[1] Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK;Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Mile End, London, E1 4NS, UK

关键词: Intraflagellar transport;    Prolyl hydroxylase;    Chondrocyte;    Inflammation;    Interleukin-1;    Cytokine;    Hypoxia-inducible factor;    Primary cilium;   

Others  :  791075
DOI  :  10.1186/2046-2530-2-17

 received in 2013-09-10, accepted in 2013-11-19,  发布年份 2013

【 摘 要 】

Background

The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling.

Results

Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition.

Conclusions

These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation.

【 授权许可】

   
2013 Wann et al.; licensee BioMed Central Ltd.

【 图 表 】

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