Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti‐inflammatory effect

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Abstract
We have reported that andrographolide (ANDRO), an active component of Andrographis paniculata, inhibits inflammatory responses by rat neutrophils. To further elucidate the possible mechanism(s) underlying the ANDRO's effect, N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐induced adhesion and transmigration of isolated peripheral human neutrophils were studied. Pretreatment with ANDRO (0.1–10 μM) concentration‐dependently prevented fMLP‐induced neutrophil adhesion and transmigration. We further examined the up‐expression of surface Mac‐1 (CD11b/CD18), an essential integrin mediated in neutrophil adhesion and transmigration. ANDRO pretreatment significantly decreased fMLP‐induced up‐expression of both CD11b and CD18. Accumulation of reactive oxygen species (ROS) as well as quick intracellular calcium ([Ca++]i) mobilization induced by fMLP displays two important signalling pathways in regulating the up‐expression of Mac‐1 by neutrophils. That ANDRO pretreatment diminished fMLP‐induced production of H2O2 and O2.−, but failed to block that of [Ca++]i mobilization suggested that the ROS but not [Ca++]i signalling could be modulated by ANDRO. To clarify whether ROS production impeded by ANDRO could be an antagonism of fMLP binding, phorbol‐12‐myristate‐13‐acetate (PMA), a direct protein kinase C (PKC) activator, was introduced to activate ROS production. PMA triggered remarkable ROS production and adhesion, and were partially reversed by ANDRO. This indicated that a PKC‐dependent mechanism might be interfered by ANDRO. We conclude that the prevention of ROS production through, at least in part, modulation of PKC‐dependent pathway could confer ANDRO the ability to down‐regulate Mac‐1 up‐expression that is essential for neutrophil adhesion and transmigration. British Journal of Pharmacology (2002) 135, 399–406; doi:10.1038/sj.bjp.0704493

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