Increasing evidence has demonstrated that
Toll-like receptor 4 (TLR4) -mediated
systemic inflammatory response syndrome accompanied by
multiple organ failure, is one of the most common causes of death in patients with severe
acute pancreatitis. Recent reports have revealed that heparan sulphate (HS)
proteoglycan, a component of extracellular matrices, potentiates the activation of intracellular pro-inflammatory responses via TLR4, contributing to the aggravation of
acute pancreatitis. However, little is known about the participants in the HS/TLR4-mediated inflammatory cascades. Our previous work provided a clue that a membrane
potassium channel (MaxiK) is responsible for HS-induced production of inflammatory
cytokines. Therefore, in this report we attempted to reveal the roles of MaxiK in the activation of macrophages stimulated by HS. Our results showed that incubation of RAW264.7 cells with HS up-regulated MaxiK and TLR4 expression levels. HS could also activate
MaxiK channels to promote the efflux of
potassium ions from cells, as measured by the elevated activity of caspase-1, whereas this was significantly abolished by treatment with
paxilline, a specific blocker of the
MaxiK channel. Moreover, it was found that
paxilline substantially inhibited HS-induced activation of several different
transcription factors in macrophages, including nuclear factor-κB, p38 and
interferon regulatory factor-3, followed by decreased production of tumour
necrosis factor-α and
interferon-β. Taken together, our investigation provides evidence that the HS/TLR4-mediated intracellular inflammatory cascade depends on the activation of MaxiK, which may offer an important opportunity for a new approach in therapeutic strategies of severe
acute pancreatitis.