Research ArticleInflammation

Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling

Sci. Signal.  15 Mar 2016:
Vol. 9, Issue 419, pp. ra28
DOI: 10.1126/scisignal.aad2357

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The proinflammatory cytokine interleukin-23 (IL-23), which is composed of the p19 and p40 subunits and produced by macrophages and dendritic cells, is implicated in inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis. Endothelial cells make only the p19 protein and so cannot produce IL-23. When examining adventitial capillaries from patients with the inflammatory disease giant-cell arteritis (GCA), Espígol-Frigolé et al. found that p19 associated with the cytokine receptor signaling subunit gp130 intracellularly in endothelial cells. This association activated STAT3 signaling and increased the cell surface abundance of adhesion molecules, which led to the transendothelial migration of lymphocytes in vitro. Together, these results suggest that p19 signals alone within endothelial cells to promote inflammation and that it may provide a therapeutic target to treat GCA and other related diseases.

Abstract

Interleukin-23 (IL-23), a heterodimeric cytokine composed of the unique p19 peptide (IL-23p19) and a peptide called IL-12p40, which is shared with IL-12, is implicated in Crohn’s disease, rheumatoid arthritis, psoriasis, and other immune-mediated inflammatory diseases. Endothelial cells produce the IL-23p19 peptide in the absence of the IL-12p40 chain and thus do not make heterodimeric IL-23. We found that intercellular IL-23p19 increased the cell surface abundances of intercellular adhesion molecule–1 (ICAM-1) and vascular cell adhesion molecule–1 (VCAM-1) on endothelial cells, which enhanced the attachment of leukocytes and increased their transendothelial migration. Intracellular p19 associated with the cytokine receptor subunit gp130 and stimulated the gp130-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling. Proinflammatory factors promoted the generation of IL-23p19 in endothelial cells. The adventitial capillaries of inflamed temporal arteries in patients with giant-cell arteritis (GCA) had endothelial p19 protein associated with gp130, but did not contain the IL-12p40 chain. Because adventitial capillaries are essential for the entry of inflammatory cells into arterial walls, these data suggest that p19 may contribute to GCA disease and could represent a therapeutic target. Our results provide evidence that IL-23p19 is a previously unrecognized endothelial proinflammatory peptide that promotes leukocyte transendothelial migration, advancing our current understanding of the complexities of inflammatory responses.

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