Monday, March 21, 2016

IL-23p19 has an inside job in endothelial cells

IL-12 cytokine family is full of surprises. Ordinarily, these cytokines (IL-12, IL-23, IL-27, IL-35) are made of two heterodimeric sub-units. But one after another, each of the sub-units were found to have an independent function.  

Latest in these series is a study from Science Signaling that showed that human endothelial cells express intra-cellular IL-23p19 that signals via gp130 molecules mimicking IL-6.

Initially, the authors showed that endothelial cells from Giant-cell arteritis (GCA) patients express IL-23p19 subunit, but not another IL-23p40 subunit (while I support fully-human studies, in controversial situations such as this, I preferred if the authors have included confirmation staining on IL-23p19 KO cell from KO mice or CRISPR/Cas9 edited IL-23p19 KO human cells). 

Next, in vitro experiments with primary human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) confirmed selective expression of IL-23p19 within endothelial cells in response to pro-inflammatory signaling.

IL-23p19 was detected in endothelial cell lysate but not in supernatants, suggesting that it was intra-cellular protein and wasn't secreted in culture medium.

Mechanistically, IL-23p19 transduced endothelial cells up-regulated adhesion molecules (VCAM-1, ICAM-1, PECAM-1) and induced gp130-dependent STAT3 activation.

The authors hypothesized that IL-23p19 could be similar to viral IL-6 (vIL-6), a viral cytokine product of human herpesvirus 8 (HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus).

In summary, this study provided evidence that in humans IL-23p19 could have an independent biological function in endothelial cells by promoting adhesion and recruitment of inflammatory cells thus contributed to vasculitis.

David Usharauli

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