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


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)-1beta, tumor necrosis factor-alpha (TNF-alpha), 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-1beta or TNF-alpha. 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.
Hernández-Rodríguez
José
J
Department of Internal Medicine, Hospital Clínic, University of Barcelona, Institut d'investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Segarra
Marta
M
Vilardell
Carme
C
Sánchez
Montse
M
García-Martínez
Ana
A
Esteban
María-José
MJ
Grau
Josep M
JM
Urbano-Márquez
Alvaro
A
Colomer
Dolors
D
Kleinman
Hynda K
HK
Cid
Maria C
MC
D000210:Acute-Phase Reaction; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D013700:Giant Cell Arteritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013699:Temporal Arteries / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant