Production of growth related oncogene protein-alpha in human umbilical vein endothelial cells stimulated with soluble interleukin-6 receptor-alpha: role of signal transducers, janus kinase 2 and mitogen-activated kinase kinase.

Growth-related oncogene protein-alpha (GRO-alpha) is a member of the C-X-C chemokine family with a wide variety of biological activities. We studied the production of GRO-alpha by human umbilical vein endothelial cells (HUVEC) in response to the stimulation with soluble form of interleukin-6 receptor alpha (sIL-6R). sIL-6R stimulated HUVEC to express GRO-alpha mRNA and secrete GRO-alpha protein in concentration-and time-dependent manners. The sIL-6R-induced GRO-alpha expression was inhibited by the pretreatment of the cells with AG490, a janus kinase 2 (JAK2) inhibitor, or with U0126, a MAP kinase-ERK kinase (MEK) inhibitor. sIL-6R also induced the phosphorylation of both Src homology 2-protein tyrosine phosphatase-2 (SHP-2), signal transducer and activator of transcription 3 (STAT3) and MEK. AG490 pretreatment inhibited the MEK phosphorylation but did not affect the STAT3 phosphorylation. We conclude that sIL-6R induces GRO-alpha expression in HUVEC through the activation of JAK2 and MEK.