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(Circulation. 2003;107:2428.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Elevated Production of Interleukin-6 Is Associated With a Lower Incidence of Disease-Related Ischemic Events in Patients With Giant-Cell Arteritis

Angiogenic Activity of Interleukin-6 as a Potential Protective Mechanism

José Hernández-Rodríguez, MD; Marta Segarra, GS; Carme Vilardell, MD; Montse Sánchez, RN; Ana García-Martínez, MD; María-José Esteban, MD; Josep M. Grau, MD; Alvaro Urbano-Márquez, MD; Dolors Colomer, PhD; Hynda K. Kleinman, PhD; Maria C. Cid, MD

From the Vasculitis Research Unit, Departments of Internal Medicine (J.H.-R., M. Segarra, C.V., A.G.-M., M.-J.E., J.M.G., A.U.-M., M.C.C.), Pathology (M. Sánchez), and Hematopathology (D.C.), Hospital Clínic, University of Barcelona, Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, and Craniofacial Development and Regeneration Branch (H.K.K.), National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md.

Correspondence to Maria C. Cid, MD, Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. E-mail mccid{at}clinic.ub.es

Background— Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events.

Methods and Results— To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1ß, tumor necrosis factor- (TNF-), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9±2.1 versus 27.6±7.8 relative units, P=0.013), lower IL-6 immunohistochemical expression scores (1.5±0.9 versus 2.7±1, P=0.001), and lower circulating levels of IL-6 (13.6±2.1 versus 24±2.4 pg/mL, P=0.002) than patients without ischemic complications. No significant differences were found for either IL-1ß or TNF-. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays.

Conclusions— GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA.

Key Words: angiogenesis • interleukins • ischemia • inflammation

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