Published Online
on May 12, 2003

A more recent version of this article appeared on May 20, 2003

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Submitted on October 17, 2002
Revised on February 28, 2003
Accepted on February 28, 2003

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, and 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.

^* To whom correspondence should be addressed. 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)-1, 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-1 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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