title: Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation.
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.
authors.affiliation: Department of Medicine, Oncology and Clinical Immunology Unit, H San Raffaele University Hospital, DIBIT 3A1, via Olgettina 58, 20132 Milano, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Comite
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Rossi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marinosci
authors.forename: Karine
authors.initials: K
authors.lastname: Lolmede
authors.forename: Elena
authors.initials: E
authors.lastname: Baldissera
authors.forename: Patrizia
authors.initials: P
authors.lastname: Aiello
authors.forename: Ruediger B
authors.initials: RB
authors.lastname: Mueller
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Sabbadini
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D053379:Chromogranin A / Q000097:blood* / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D055806:Microvessels / Q000166:cytology; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology; D011446:Prospective Studies; D011658:Pulmonary Fibrosis / Q000503:physiopathology; D012700:Serositis / Q000503:physiopathology; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology; D014657:Vasculitis / Q000503:physiopathology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053379:Chromogranin A; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1