Signaling mechanisms of interleukin‐4‐induced pro‐inflammatory pathways in human vascular endothelial cells

Abstract

It has been proposed that two major signal transduction pathways such as Janus kinase (JAK)-signal transducers and activators of transcription (STAT) and phosphoinositide-3 kinase (PI3K) are involved in the signaling cascade initiated by IL-4. Emerging evidence has also established the p38 mitogen-activated protein kinase (MAPK) pathway as one element of the IL-4 signaling cascade. The present study was designed to examine the hypothesis that interleukin-4 (IL-4) may induce pro-inflammatory pathways through activation of p38 MAPK in human vascular endothelial cells (HUVEC). The quantitative real-time RT-PCR showed that selective inhibitors for JAK/STAT and PI3K signaling pathways significantly attenuated overexpression of pro-inflammatory mediators in IL-4-stimulated HUVEC. In addition, p38 MAP kinase inhibitor SB202190 significantly and dose-dependently inhibited IL-4-mediated up-regulation of mRNA and protein expression of pro-inflammatory cytokine (interleukin-6), chemokine (monocyte chemoattractant protein-1) and adhesion molecules (vascular cell adhesion molecule-1 and E-selectin) in HUVEC. These results provide new evidence to indicate that IL-4 can induce pro-inflammatory vascular environment through the p38 MAPK-mediated signaling pathways. These data may contribute to understanding the cellular and molecular signaling mechanisms involved in IL-4-mediated progression of atherosclerosis and development of therapeutic strategies for the prevention of atherosclerotic lesion (This work was supported by the American Heart Association Ohio Valley Affiliate).