IL‐22 has a pathogenetic role in psoriasis, where it is responsible for the altered proliferation and differentiation of keratinocytes and induces inflammatory molecules. The IL‐22‐induced effects are mediated by STAT3, whose activity is proportional to acetylation in lysine (Lys)685 and phosphorylation in tyrosine (Tyr)705. Lys 685 acetylation of STAT3 is inhibited by sirtuin (SIRT)1, a class III deacetylase promoting keratinocyte differentiation. Due to the opposite effects of IL‐22 and SIRT1, we investigated whether IL‐22‐induced effects in keratinocytes could be regulated by SIRT1 through control of STAT3. We found that SIRT1 opposes the IL‐22‐induced STAT3 activity by deacetylating STAT3 and reducing STAT3 Tyr705 phosphorylation. By controlling STAT3, SIRT1 also influences the IL‐22‐induced expression of molecules involved in proliferation and inflammation as well as proliferation and migration processes in cultured keratinocytes. Although SIRT1 levels were similar in keratinocytes of healthy individuals and patients with psoriasis, they were reduced in psoriatic skin lesions, with the lymphokine IFN‐γ inhibiting SIRT1 expression. Concomitantly, IFN‐γ enhanced basal acetylation of STAT3 and its phosphorylation induced by IL‐22. In conclusion, STAT3‐dependent IL‐22 signaling and effects in keratinocytes are negatively regulated by SIRT1. In skin affected by psoriasis, SIRT1 is down‐regulated by IFN‐y, which thus renders psoriatic keratinocytes more prone to respond to IL‐22.—Sestito, R., Madonna, S., Scarponi, C., Cianfarani, F., Failla, C. M., Cavani, A., Girolomoni, G., Albanesi, C. STAT3‐dependent effects of IL‐22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation. FASEB J. 25, 916–927 (2011). www.fasebj.org

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for several growth factors of the VEGF family. Endothelial cells express a membrane-spanning form of VEGFR-1 and secrete a soluble variant of the receptor comprising only the extracellular region. The role of this variant has not yet been completely defined. In this study, we report that the secreted VEGFR-1 is present within the extracellular matrix deposited by endothelial cells in culture, suggesting a possible involvement in endothelial cell adhesion and migration. In adhesion assays, VEGFR-1 extracellular region specifically promoted endothelial cell attachment. VEGFR-1-mediated cell adhesion was divalent cation-dependent, and inhibited by antibodies directed against the α5β1 integrin. Moreover, VEGFR-1 promoted endothelial cell migration, and this effect was inhibited by anti-α5β1 antibodies. Direct binding of VEGFR-1 to theα5β1 integrin was also detected. Finally, binding to VEGFR-1 initiated endothelial cell spreading. Altogether these results indicate that the soluble VEGFR-1 secreted by endothelial cells becomes a matrix-associated protein that is able to interact with the α5β1 integrin, suggesting a new role of VEGFR-1 in angiogenesis, in addition to growth factor binding.

Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling. In agreement with this activity, high levels of circulating sVEGFR-1 or sFlt1-14 are associated with different pathological conditions involving vascular dysfunction. Moreover, sVEGFR-1 and sFlt1-14 have an additional role in angiogenesis: they are deposited in the endothelial cell and pericyte extracellular matrix, and interact with cell membrane components. Interaction of sVEGFR-1 with α5β1 integrin on endothelial cell membranes regulates vessel growth, triggering a dynamic, pro-angiogenic phenotype. Interaction of sVEGFR-1/sFlt1-14 with cell membrane glycosphingolipids in lipid rafts controls kidney cell morphology and glomerular barrier functions. These cell–matrix contacts represent attractive novel targets for pharmacological intervention in addition to those addressing interactions between VEGFs and their receptors.