OBJECTIVE :: IL-27 belongs to the IL-12 family of cytokines and is recognized for its role in Th cell differentiation and as an inhibitor of tumor angiogenesis. The purpose of this study was to investigate the effect of IL-27 on proliferation of lymphatic endothelial cells to gain insight into the interplay between the immune system and development of the lymphatic system. METHODS : IL-27-stimulated signal transduction in human dermal lymphatic endothelial cells was measured by western blotting and synthesis of CXCL10 and CXCL11 by use of RT-PCR and ELISA. Proliferation was measured using MTT and BrdU kits and the role
of STAT1 and chemokines was determined by use of siRNA and recombinant proteins. RESULTS : Stimulation of lymphatic endothelial cell cultures with
IL-27 induced JAK dependent phosphorylation of STAT1 and STAT3
and inhibited lymphatic endothelial cell proliferation and migration.
Expression of CXCL10 and CXCL11, both STAT1 target genes, was profoundly up-regulated upon IL-27 stimulation, and recombinant
CXCL10 and CXCL11 inhibited FGF-2-induced proliferation in vitro.
siRNA targeting of STAT1 almost completely abrogated CXCL10 and
CXCL11 expression as well as the proliferative effect of IL-27.
CONCLUSIONS : IL-27 function as an anti-lymphangiogenic regulator
in vitro by up-regulating chemokines and interfering with the
mitogenic effect of growth factors through STAT1 activation.