Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0608358 on October 2, 2008

Published online before print October 2, 2008
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(Journal of Leukocyte Biology. 2009;85:81-87.)
© 2009 by Society for Leukocyte Biology

Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-{alpha}-elicited endothelial activation

Gabriele Di Comite*, Carlo M. Rossi*, Alessandro Marinosci*, Karine Lolmede*, Elena Baldissera*, Patrizia Aiello*, Ruediger B. Mueller{dagger}, Martin Herrmann{dagger}, Reinhard E. Voll{ddagger}, Patrizia Rovere-Querini*, Maria Grazia Sabbadini*, Angelo Corti*,§ and Angelo A. Manfredi*,1

* Departments of Medicine, Oncology and Clinical Immunology Unit, H San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, and
§ IIT Network-Molecular Neuroscience Unit, Milan, Italy;
{dagger} Department of Internal Medicine III and
{ddagger} IZKF Research Group 2, Nikolaus-Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Erlangen, Germany

1 Correspondence: Departments of Medicine, Oncology and Clinical Immunology Unit, H San Raffaele University Hospital, DIBIT 3A1, via Olgettina 58, 20132 Milano, Italy. E-mail: manfredi.angelo{at}hsr.it

ABSTRACT

TNF-{alpha} plays an important role in the natural history of rheumatoid arthritis (RA), a systemic disease characterized by endothelial activation and synovial involvement with bone erosions. Neuroendocrine signals contribute as well to RA, but their role is poorly understood. We measured in 104 RA patients and in an equal number of sex- and age-matched, healthy controls the blood levels of chromogranin A (CgA), a candidate marker linking the neuroendocrine system to TNF-{alpha}-mediated vascular inflammation. CgA levels were significantly higher in patients with RA and remained stable over time. High levels of CgA were significantly associated with severe extra-articular manifestations, namely pulmonary fibrosis, rheumatoid vasculitis, serositis, and peripheral neuropathy. RA sera curbed the response of human microvascular endothelial cells to TNF-{alpha}, as assessed by the expression of ICAM-1, the release of MCP-1/CCL2, and the export of nuclear high-mobility group box 1; the effect abated in the presence of anti-CgA antibodies. The efficacy of the blockade was significantly correlated with the CgA concentration in the serum. The recombinant aminoterminal portion of CgA, corresponding to residues 1–78, had similar inhibitory effects on endothelial cells challenged with TNF-{alpha}. Our results suggest that enhanced levels of CgA identify patients with extra-articular involvement and reveal a negative feedback loop that limits the activation of endothelial cells in RA.

Key Words: arthritis • inflammation • HMGB1 • cell activation • neuropeptides




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