Arachidonic Acid Regulates the Translocation of 5-Lipoxygenase to the Nuclear Membranes in Human Neutrophils

Elevation of the intracellular cAMP concentration in agonist-activated human neutrophils (PMN) leads to the concomitant inhibitions of arachidonic acid (AA) release, 5-lipoxygenase (5-LO) translocation, and leukotriene (LT) biosynthesis. We report herein that exogenous AA completely prevents cAMP-dependent inhibition of 5-LO translocation and LT biosynthesis in agonist-activated PMN. Moreover, the group IVA phospholipase A2 inhibitor pyrrophenone and the MEK inhibitor U-0126 inhibited AA release and 5-LO translocation in activated PMN, and these effects were also prevented by exogenous AA, demonstrating a functional link between AA release and 5-LO translocation. Polyunsaturated fatty acids of the C18 and C20 series containing to the were AA in 5-LO translocation in agonist-activated PMN. the inhibitor and the intracellular that the 5-LO translocation and the and 5-LO and AA to the pyrrophenone inhibition of 5-LO translocation, that the of of 5-LO translocation by AA in the of the report that AA the translocation of 5-LO in human and a of the inhibition of LT biosynthesis. Elevation of the intracellular cAMP concentration in agonist-activated human neutrophils (PMN) leads to the concomitant inhibitions of arachidonic acid (AA) release, 5-lipoxygenase (5-LO) translocation, and leukotriene (LT) biosynthesis. We report herein that exogenous AA completely prevents cAMP-dependent inhibition of 5-LO translocation and LT biosynthesis in agonist-activated PMN. Moreover, the group IVA phospholipase A2 inhibitor pyrrophenone and the MEK inhibitor U-0126 inhibited AA release and 5-LO translocation in activated PMN, and these effects were also prevented by exogenous AA, demonstrating a functional link between AA release and 5-LO translocation. Polyunsaturated fatty acids of the C18 and C20 series containing to the were AA in 5-LO translocation in agonist-activated PMN. the inhibitor and the intracellular that the 5-LO translocation and the and 5-LO and AA to the pyrrophenone inhibition of 5-LO translocation, that the of of 5-LO translocation by AA in the of the report that AA the translocation of 5-LO in human and a of the inhibition of LT biosynthesis. LT cAMP IVA phospholipase fatty acid cAMP IVA phospholipase fatty acid of in and and of LT and of LT biosynthesis and the release of AA by the AA by the 5-LO to the of to by and in the of the a and of human LT biosynthesis in of the the the of 5-LO that 5-LO the to to by 5-LO to that 5-LO the to to the that 5-LO a to the and the of the to and the translocation of the in the of 5-LO and translocation to the of 5-LO in functional to LT biosynthesis in of in LT biosynthesis and that a AA and acid to the Moreover, and to LT biosynthesis the translocation of 5-LO to in activated a of and of 5-LO by and of 5-LO and also in the of 5-LO LT in in the of 5-LO translocation to the in activated by and and that intracellular cAMP concentration and that also inhibited the release of AA in activated human that the translocation of 5-LO to the the release of AA in human the AA a in the of 5-LO in human acid acid acid acid acid acid acid acid acid acid and were AA were and and were 5-LO and were a of a of MEK and were and were of and were the and the were by were the by the to the the were in containing were were and were of were were of AA release by the inhibitor were and pyrrophenone and were of the the of LT biosynthesis by in were by the of of and were and were the of 5-LO and and AA the of 5-LO and AA, were of a containing of and AA the also of were to the and the were and by the of and and and and to 5-LO AA the were to a and in of by in the of 5-LO and were of and and to the and and were to were by were and were by were in containing 5-LO and a and the 5-LO and that the of LT biosynthesis in inhibition of AA release Moreover, that of LT the translocation of also and inhibited by a between inhibition of AA release and 5-LO translocation in human series of to the of AA in the inhibition of 5-LO translocation. in and the in inhibited 5-LO translocation and LT biosynthesis in and in of exogenous AA of LT biosynthesis and 5-LO translocation in the of a functional link between AA release and 5-LO translocation in activated human that were in 5-LO in by and to and to a and to that the effects of AA human in of AA to human a 5-LO translocation, and LT by and in that in agonist-activated and that the in AA release and LT biosynthesis in activated the the of AA in 5-LO translocation, the of the and inhibitor pyrrophenone LT biosynthesis and 5-LO translocation. that LT biosynthesis inhibited by pyrrophenone in and human 5-LO translocation completely in and and of pyrrophenone 5-LO translocation LT by the of AA of the inhibitor pyrrophenone 5-LO translocation in activated human human were pyrrophenone AA, were and the of 5-LO and 5-LO in and of that the in the that the MEK and U-0126 of and AA release in also that these MEK 5-LO translocation in human the of and U-0126 AA release and 5-LO translocation in activated that U-0126 AA release in agonist-activated in a were inhibition of AA release the inhibition of and 5-LO translocation and of AA to the the translocation of 5-LO the of that the of MEK 5-LO translocation the of AA release of the MEK and AA release, and 5-LO translocation in activated human human were the MEK U-0126 were by the of of containing of and of and AA the by and by the of and were U-0126 AA and were by the of of and were and were and the of and 5-LO of of the of AA 5-LO were to the of the of AA 5-LO translocation. these the inhibitor pyrrophenone to AA release and 5-LO translocation in in these the of 5-LO translocation by exogenous fatty acids the of the of fatty acids of the C20 series AA and were of 5-LO translocation, and 5-LO translocation in activated the acids 5-LO translocation, the were in 5-LO translocation in activated the biosynthesis of and were in of and were to the of of the and 5-LO translocation in and and 5-LO translocation to the and also 5-LO translocation, to a and and were to were fatty acids of the C18 series the 5-LO translocation in of to that by AA the concentration and 5-LO translocation, a of AA and 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5-LO translocation in human human were in of pyrrophenone and and the were and of 5-LO and 5-LO were in and of of intracellular 5-LO translocation the in the 5-LO translocation in of AA were inhibited by in the 5-LO translocation that the 5-LO translocation by the exogenous and 5-LO in to the 5-LO translocation a in and 5-LO translocation in inhibited by the the 5-LO translocation in of of the in inhibited by that the 5-LO translocation a of these fatty acids and 5-LO of the intracellular and the 5-LO translocation in human were and the of and AA human were and the of and AA, were and of 5-LO and 5-LO were in and of the of and in LT biosynthesis the of a LT the translocation of 5-LO to the and that leads to inhibition of AA release in activated Moreover, that in LT 5-LO translocation, also inhibited by in activated that of IVA the and inhibited AA release and 5-LO translocation in activated to the of a between these that AA a of a of 5-LO in inhibition of AA that the of AA 5-LO translocation and LT biosynthesis in the AA release and 5-LO translocation of that the and inhibitor completely AA release and LT biosynthesis in activated also 5-LO these effects of pyrrophenone were by exogenous AA, of the inhibitor 5-LO translocation. that the MEK U-0126 and AA release and 5-LO translocation in agonist-activated and that the by exogenous these to a of AA in the of 5-LO translocation in and a functional between the and the also a by cAMP 5-LO in of in inhibition of AA release, in to a the translocation of the in LT biosynthesis. 5-LO and that 5-LO in of 5-LO the to the that 5-LO translocation in human that of 5-LO in human the in inhibition of LT biosynthesis. in the in the the and and release in human that phospholipase in the effects of of the effects of fatty acids 5-LO translocation in the the that fatty acids 5-LO translocation, to the the that were AA in 5-LO translocation, and the of a of the of AA by the the that AA the of 5-LO translocation. of the 5-LO inhibitor completely 5-LO the translocation of demonstrating that AA by 5-LO 5-LO translocation that also to 5-LO translocation. these to a of in the of AA to 5-LO translocation, and that between the of to 5-LO translocation and to 5-LO by and 5-LO to 5-LO 5-LO by the of also that AA and acid 5-LO AA to AA the in and to these that the of AA 5-LO translocation herein of and 5-LO in acid to 5-LO translocation in the and that the of AA 5-LO translocation in activated herein the of of the in the 5-LO translocation to the in and prevented by the inhibitor the that that the of the of AA 5-LO translocation. in the of fatty acids and to 5-LO translocation in in to AA, that 5-LO translocation in the the AA the and inhibited the of to in 5-LO translocation the 5-LO AA a the of AA 5-LO translocation. of of the and the the inhibitor to 5-LO in and in in that the and the AA 5-LO a of AA the 5-LO inhibitor to the of these 5-LO to the to the of 5-LO and that AA, and translocation of 5-LO in pyrrophenone and that the of AA in 5-LO translocation the 5-LO in of the that the the of the that 5-LO to of the of 5-LO a to in and a and to 5-LO translocation in of the inhibition by of 5-LO translocation the by in the translocation of 5-LO in of by AA of 5-LO translocation to the in activated also a AA, and a functional between the and the of the 5-LO in these to a by LT biosynthesis in human LT cAMP IVA phospholipase fatty acid cAMP IVA phospholipase fatty acid of in and and of LT and of LT biosynthesis and the release of AA by the AA by the 5-LO to the of to by and in the of the a and of human PMN. leukotriene intracellular cAMP concentration acid acid acid 5-lipoxygenase arachidonic acid acid acid acid acid acid acid group IVA phospholipase A2 acid acid fatty acid acid leukotriene intracellular cAMP concentration acid acid acid 5-lipoxygenase arachidonic acid acid acid acid acid acid acid group IVA phospholipase A2 acid acid fatty acid acid LT biosynthesis in of the the the of 5-LO that 5-LO the to to by 5-LO to that 5-LO the to to the that 5-LO a to the and the of the to and the translocation of the in the of 5-LO and translocation to the of 5-LO in functional to LT biosynthesis in of in LT biosynthesis and that a AA and acid to the Moreover, and to LT biosynthesis the translocation of 5-LO to in activated a of and of 5-LO by and of 5-LO and also in the of 5-LO LT in in We the of 5-LO translocation to the in activated by and and that intracellular cAMP concentration and that also inhibited the release of AA in activated human that the translocation of 5-LO to the the release of AA in human the AA a in the of 5-LO in human acid acid acid acid acid acid acid acid acid acid and were AA were and and were 5-LO and were a of a of MEK and were and were of and were the and the were by were the by the to the the were in containing were were and were of were were of AA release by the inhibitor were and pyrrophenone and were of the the of LT biosynthesis by in were by 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the 5-LO and that the of LT biosynthesis in inhibition of AA release Moreover, that of LT the translocation of also and inhibited by a between inhibition of AA release and 5-LO translocation in human series of to the of AA in the inhibition of 5-LO translocation. in and the in inhibited 5-LO translocation and LT biosynthesis in and in of exogenous AA of LT biosynthesis and 5-LO translocation in the of a functional link between AA release and 5-LO translocation in activated human that were in 5-LO in by and to and to a and to that the effects of AA human in of AA to human a 5-LO translocation, and LT by and in that in agonist-activated and that the in AA release and LT biosynthesis in activated the the of AA in 5-LO translocation, the of the and inhibitor pyrrophenone LT biosynthesis and 5-LO translocation. that LT biosynthesis inhibited by pyrrophenone in and human 5-LO translocation completely in and and of pyrrophenone 5-LO translocation LT by the of AA that the in the that the MEK 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translocation in 5-LO 5-LO the of the of the of AA 5-LO translocation, and the of the of were 5-LO the to to the of the the 5-LO were the in and to a 5-LO translocation in the 5-LO 5-LO translocation that the of the the 5-LO translocation of the to were a 5-LO inhibitor the also that and AA to 5-LO translocation by of in the of these the of 5-LO also that of 5-LO translocation by the the of by We also the inhibitor to 5-LO translocation in activated that to the 5-LO the 5-LO translocation in a in and 5-LO acid also 5-LO translocation and and the and and of intracellular 5-LO translocation the in the 5-LO translocation in of AA were inhibited by in the 5-LO translocation that the 5-LO translocation by the exogenous and 5-LO in to the 5-LO translocation a in and 5-LO translocation in inhibited by the the 5-LO translocation in of of the in inhibited by that the 5-LO translocation a of these fatty acids and 5-LO the of and in LT biosynthesis the of a LT the translocation of 5-LO to the and that leads to inhibition of AA release in activated Moreover, that in LT 5-LO translocation, also inhibited by in activated that of IVA the and inhibited AA release and 5-LO translocation in activated to the of a between these that AA a of a of 5-LO in inhibition of AA that the of AA 5-LO translocation and LT biosynthesis in the AA release and 5-LO translocation of that the and inhibitor completely AA release and LT biosynthesis in activated also 5-LO these effects of pyrrophenone were by exogenous AA, of the inhibitor 5-LO translocation. that the MEK U-0126 and AA release and 5-LO translocation in agonist-activated and that the by exogenous these to a of AA in the of 5-LO translocation in and a functional between the and the also a by cAMP 5-LO in of in inhibition of AA release, in to a the translocation of the in LT biosynthesis. 5-LO and that 5-LO in of 5-LO the to the that 5-LO translocation in human that of 5-LO in human the in inhibition of LT biosynthesis. in the in the the and and release in human that phospholipase in the effects of of the effects of fatty acids 5-LO translocation in the the that fatty acids 5-LO translocation, to the the that were AA in 5-LO translocation, and the of a of the of AA by the the that AA the of 5-LO translocation. of the 5-LO inhibitor completely 5-LO the translocation of demonstrating that AA by 5-LO 5-LO translocation that also to 5-LO translocation. these to a of in the of AA to 5-LO translocation, and that between the of to 5-LO translocation and to 5-LO by and 5-LO to 5-LO 5-LO by the of also that AA and acid 5-LO AA to AA the in and to these that the of AA 5-LO translocation herein of and 5-LO in acid to 5-LO translocation in the and that the of AA 5-LO translocation in activated herein the of of the in the 5-LO translocation to the in and prevented by the inhibitor the that that the of the of AA 5-LO translocation. in the of fatty acids and to 5-LO translocation in in to AA, that 5-LO translocation in the the AA the and inhibited the of to in 5-LO translocation the 5-LO AA a the of AA 5-LO translocation. of of the and the the inhibitor to 5-LO in and in in that the and the AA 5-LO a of AA the 5-LO inhibitor to the of these 5-LO to the to the of 5-LO and that AA, and translocation of 5-LO in pyrrophenone and that the of AA in 5-LO translocation the 5-LO in of the that the the of the that 5-LO to of the of 5-LO a to in and a and to 5-LO translocation in of the inhibition by of 5-LO translocation the by in the translocation of 5-LO in of by AA of 5-LO translocation to the in activated also a AA, and a functional between the and the of the 5-LO in these to a by LT biosynthesis in human the of and in LT biosynthesis the of a LT the translocation of 5-LO to the We and that leads to inhibition of AA release in activated Moreover, that in LT 5-LO translocation, also inhibited by in activated that of IVA the and inhibited AA release and 5-LO translocation in activated to the of a between these that AA a of a of 5-LO translocation. in inhibition of AA that the of AA 5-LO translocation and LT biosynthesis in the AA release and 5-LO translocation of that the and inhibitor completely AA release and LT biosynthesis in activated also 5-LO these effects of pyrrophenone were by exogenous AA, of the inhibitor 5-LO translocation. that the MEK U-0126 and AA release and 5-LO translocation in agonist-activated and that the by exogenous these to a of AA in the of 5-LO translocation in and a functional between the and the also a by cAMP 5-LO in of in inhibition of AA release, in to a the translocation of the in LT biosynthesis. 5-LO and that 5-LO in of 5-LO the to the that 5-LO translocation in human that of 5-LO in human the in inhibition of LT biosynthesis. in the in the the and and release in human that phospholipase in the effects of of the effects of fatty acids 5-LO translocation in the the that fatty acids 5-LO translocation, to the the that were AA in 5-LO translocation, and the of a of the of AA by the the that AA the of 5-LO translocation. of the 5-LO inhibitor completely 5-LO the translocation of demonstrating that AA by 5-LO 5-LO translocation that also to 5-LO translocation. these to a of in the of AA to 5-LO translocation, and that between the of to 5-LO translocation and to 5-LO by and 5-LO to 5-LO translocation. 5-LO by the of also that AA and acid 5-LO AA to AA the in and to these that the of AA 5-LO translocation herein of and 5-LO in acid to 5-LO translocation in the and that the of AA 5-LO translocation in activated herein the of of the in the 5-LO translocation to the in and prevented by the inhibitor the that that the of the of AA 5-LO translocation. in the of fatty acids and to 5-LO translocation in in to AA, that 5-LO translocation in the the AA the and inhibited the of to in 5-LO translocation the 5-LO AA a the of AA 5-LO translocation. of of the and the the inhibitor to 5-LO in and in in that the and the AA 5-LO a of AA the 5-LO inhibitor to the of these 5-LO to the to the of 5-LO and that AA, and translocation of 5-LO in pyrrophenone and that the of AA in 5-LO translocation the 5-LO in of the that the the of the that 5-LO to of the of 5-LO a to in and a and to 5-LO translocation in of the inhibition by of 5-LO translocation the by in the translocation of 5-LO in of by AA of 5-LO translocation to the in activated also a AA, and a functional between the and the of the 5-LO in these to a by LT biosynthesis in human

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