Molecular mechanisms in lipopolysaccharide-induced interleukin 6 release in lymphatic endothelial cells

The lymphatic vasculature is involved in the transportation of tissue fluids, extravasated plasma proteins and cells back into blood circulation. Formation of lymphatic vessels by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including inflammation, lymphedema and tumor metastasis. Recent reports demonstrated that lymphatic vasculature is not just a major conduit for immune cell transport. It seems to be directly involved in both the induction and the resolution of inflammation. However, little is known about how lymphatic vessels themselves respond to inflammation. The purpose of this study was to investigate the molecular mechanism by which interleukin-6 release in LECs exposure to lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. LPS was shown to cause an increase in IL-6 release in LECs. Pharmacological inhibitors of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38MAPK or c-jun N-terminal kinase (JNK), significantly abrogated the LPS-induced IL-6 release. In addition, LPS was shown to activate ERK, p38MAPK and JNK in LECs, suggesting functional cross-talk. The results of reporter assay further indicated that LPS increased the transcriptional activity of NF-κB, a critical transcription factor in inducing IL-6 expression. Our data suggest that MAPKs and NF-κB activation may contribute to LPS-induced IL-6 release in LECs. Interventions of MAPKs and NF-κB signaling may be beneficial in the treatment of lymphatic-associated inflammation.