Beschreibung:
<jats:p>Elevated plasma IL‐6 levels are associated with an increased risk for coronary heart disease; however, causality remains undefined. We previously reported that COX‐2‐dependent PGE<jats:sub>2</jats:sub> synthesis and binding to EP4 stimulates macrophage MMP‐9 expression, which has been implicated in the pathogenesis of vascular diseases. In the present studies, we determined whether IL‐6 regulates the COX‐2→PGE<jats:sub>2</jats:sub>→EP4 receptor axis in macrophages. Results demonstrate that IL‐6 inhibited macrophage expression of 15‐PDGH, and stimulated expression of COX‐2 and mPGES‐1, resulting in an increase in PGE<jats:sub>2</jats:sub> levels. Likewise, IL‐6‐induced MMP‐9 expression in macrophages. Whereas, the COX‐2 inhibitor celecoxib completely blocked IL‐6 induced PGE<jats:sub>2</jats:sub> synthesis, MMP‐9 expression was partially attenuated. These data reveal COX‐2‐ dependent and independent mechanisms through which IL‐6 stimulates MMP‐9 expression. Engagement of the IL‐6 receptor triggers activation of the JAK/STAT and MAPK pathways leading to the expression of target genes. Pre‐incubation of macrophages with the JAK inhibitor tofacitinib blocked expression of several IL‐6‐induced genes, but paradoxically stimulated MMP‐9 expression. In contrast, MMP‐9 expression was completely blocked by the MEK inhibitor U0126. Thus, inhibition of MAPK emerges as a major strategy to block IL‐6‐induced MMP‐9 expression in macrophages. These studies were supported by HL093331.</jats:p>