N-formyl-methionyl-leucyl-phenylalanine(fMLF),itsmethylesterfMLF-OMeandinterleukin8(IL8)play a pivotalroleinneutrophilchemotaxisregulationinthelatterandearlystages,respectively,but the mechanismsthroughwhichthesignaltransductionpathwaysactivatethisfunctionarenotyet completelyunderstood.Compounds 3l and 3r, anewclassofarylcarbamoyl-imidazo-pyrazoles derivatives,weredescribedasthe first exampleofcompoundsabletoinhibithumanneutrophil chemotaxis inducedbybothfMLF-OMeandIL8.Here,wereporttheireffectsonsuperoxideproduction and lysozymerelease.Noinhibitionwasobserved,thustheycouldbedefined as “pure” chemotactic antagonists. Therefore,suchmoleculeswereusedtohighlightspecific kinasesinvolvedinneutrophil chemotaxis. Ourdataprovidesupportthatcompounds 3l and 3r stronglyinhibitp38MAPKwitheither fMLF-OMe orIL8chemoattractants,whiletheyshowdifferentsignalingpathwaysregardingPKC isoforms suggestingthata fine tuningoftheneutrophilactivationoccursthroughdifferencesinthe activationofsignalingpathways.NeitherfMLF-OMenorIL8wereabletoobtainactivationofthePI3K/ Akt pathway.Sinceanomalousactivationofneutrophilrecruitmentisoneofthecausesofmany inflammatorydiseases,thegoodversatilityofourderivativescouldrepresentthemostimportant characteristicofthesenewmoleculesinthedevelopmentofnoveltherapeutics.
Differential inhibition of signaling pathways by two new imidazo-pyrazoles molecules in fMLF-OMe- and IL8-stimulated human neutrophil
BRULLO, CHIARA;BRUNO, OLGA;
2013-01-01
Abstract
N-formyl-methionyl-leucyl-phenylalanine(fMLF),itsmethylesterfMLF-OMeandinterleukin8(IL8)play a pivotalroleinneutrophilchemotaxisregulationinthelatterandearlystages,respectively,but the mechanismsthroughwhichthesignaltransductionpathwaysactivatethisfunctionarenotyet completelyunderstood.Compounds 3l and 3r, anewclassofarylcarbamoyl-imidazo-pyrazoles derivatives,weredescribedasthe first exampleofcompoundsabletoinhibithumanneutrophil chemotaxis inducedbybothfMLF-OMeandIL8.Here,wereporttheireffectsonsuperoxideproduction and lysozymerelease.Noinhibitionwasobserved,thustheycouldbedefined as “pure” chemotactic antagonists. Therefore,suchmoleculeswereusedtohighlightspecific kinasesinvolvedinneutrophil chemotaxis. Ourdataprovidesupportthatcompounds 3l and 3r stronglyinhibitp38MAPKwitheither fMLF-OMe orIL8chemoattractants,whiletheyshowdifferentsignalingpathwaysregardingPKC isoforms suggestingthata fine tuningoftheneutrophilactivationoccursthroughdifferencesinthe activationofsignalingpathways.NeitherfMLF-OMenorIL8wereabletoobtainactivationofthePI3K/ Akt pathway.Sinceanomalousactivationofneutrophilrecruitmentisoneofthecausesofmany inflammatorydiseases,thegoodversatilityofourderivativescouldrepresentthemostimportant characteristicofthesenewmoleculesinthedevelopmentofnoveltherapeutics.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
