Mechanistic insights into XXXX -induced interleukin-8 expression: a role for oxidized phospholipid modification of apolipoprotein(a).

@entity301 @entity3452 @entity2938 @entity23601 @entity376 @entity687 @entity1366 @entity4210
UNASSIGNED: Elevated @entity3452 ( @entity3452 ) levels are a causal risk factor for @entity301 . Accumulating evidence suggests that @entity3452 can stimulate cellular inflammatory responses through the kringle-containing apolipoprotein(a) (apo(a)) component. Here, we report that recombinant apo(a) containing 17 kringle-IV domains (17K) elicits a dose-dependent increase in @entity687 mRNA and protein expression in THP-1 and U937 macrophages. This effect was blunted by mutation of the @entity376 binding site in apo(a) KIV10, which results in the loss of oxidized phospholipid (oxPL) on apo(a). Trypsin-digested 17K had the same stimulatory effect on @entity687 expression as intact apo(a) while enzymatic removal of oxPL from apo(a) significantly blunted this effect. Using siRNA to assess candidate receptors, we found that @entity4210 and @entity2938 may play roles in apo(a)-mediated @entity687 stimulation. Downstream of these receptors, inhibitors of MAP kinases JNK and @entity1366 abolished the effect of apo(a) on @entity687 gene expression. To assess roles of downstream transcription factors, luciferase reporter gene experiments were conducted using an @entity687 promoter fragment. Apo(a) induced expression of this reporter construct was eliminated by mutation of @entity687 promoter binding sites for either NF-kB or @entity23601 . Our results provide a mechanistic link between oxPL modification of apo(a) and stimulation of proinflammatory intracellular signaling pathways.
