Endocrine Abstracts

Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease. Several new therapies exist for RA but long-term patient management remains problematic.

We have discovered that hypoxia, a characteristic of inflamed tissues, potently inhibits glucocorticoid (Gc) sensitivity. This effect is mediated, in part by HIF1α, whose activity is induced in hypoxia. HIF1α gene expression is also induced in primary peripheral blood mononuclear cells (PBMCs) by inflammatory stimuli, even under normoxic conditions. HIF1α has two paralogs, HIF2α and HIF3α and several splice variants which impact on HIF function.

To determine if differences in the hypoxia signalling cascade are present in RA PBMCs were isolated from 9 healthy volunteers and 8 patients with active disease.

We find co-expression of multiple HIF1α splice variants in PBMCs and a dramatic increase in two of six HIF1α splice variants in cells activated by inflammatory stimuli in all subjects. HIF2α but not HIF3α alpha is also expressed in PBMCs, but is differentially regulated, suggesting a different control mechanism, and so a possible function in inflammation.

HIF1α target genes, including VEGF, Hexokinase 2, Interleukin 6 and Adrenomedullin (ADM), also showed increased expression in response to inflammatory stimuli. Specifically, ADM, a mainly anti-inflammatory mediator, showed significantly lower transcriptional activation in response to inflammatory stimuli in cells isolated from the RA patients compared with the healthy subjects (P=0.001).

In summary, we show activation of the hypoxia sensing cascade in PBMCs in response to inflammatory stimuli, and a dramatically deficient induction of the HIF target, and locally acting anti-inflammatory mediator ADM in patients with active RA. This inadequate induction of ADM may contribute to the progression of the chronic inflammatory response characteristic of RA.