title: Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling.
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.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Department of Systemic Autoimmune Diseases, Clinical Institute of Medicine and Dermatology, Hospital Clinic, University of Barcelona, IDIBAPS-CRB CELLEX, Barcelona 08036, Spain. georginaespigol@gmail.com tosatog@mail.nih.gov.
authors.forename: Georgina
authors.initials: G
authors.lastname: Espígol-Frigolé
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Department of Systemic Autoimmune Diseases, Clinical Institute of Medicine and Dermatology, Hospital Clinic, University of Barcelona, IDIBAPS-CRB CELLEX, Barcelona 08036, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Planas-Rigol
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ohnuki
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Salvucci
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyeongil
authors.initials: H
authors.lastname: Kwak
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Sarangan
authors.initials: S
authors.lastname: Ravichandran
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Luke
authors.affiliation: Department of Systemic Autoimmune Diseases, Clinical Institute of Medicine and Dermatology, Hospital Clinic, University of Barcelona, IDIBAPS-CRB CELLEX, Barcelona 08036, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. georginaespigol@gmail.com tosatog@mail.nih.gov.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
mesh_terms: D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C573420:ICAM1 protein, human; C508840:IL23A protein, human; D018836:Inflammation Mediators; D053760:Interleukin-23 Subunit p19; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D050822:Cytokine Receptor gp130