Department of Medicine , University of Chicago , Illinois 60637 .
Am J Physiol 268 : C604-10 ( 1995)
Abstract
Hepatic Ito cells proliferate during liver injury and fibrogenesis .
Platelet-derived growth factor ( PDGF)-induced [ 3H]thymidine incorporation was studied as Ito cells express the PDGF receptor after injury and activation .
Pretreatment with either the nonspecific lipoxygenase inhibitor ( nordihydroguaiaretic acid ) or specific inhibitors of 5-lipoxygenase ( SC-41661 and ICI-230487 ) inhibited PDGF-induced mitogenesis .
Ito cells predominantly produce the leukotriene ( LT ) C4 >> ; LTB4 .
The PDGF-induced signal transduction cascade was studied to determine the potential mechanism of action of the lipoxygenase inhibitors .
It was found that PDGF receptor abundance and receptor activation were not altered by lipoxygenase inhibition , suggesting that a postreceptor mechanism was involved .
The two-key cytoplasmic serine-threonine kinases Raf and MAPK ( mitogen-activated protein kinase ) , which are induced by PDGF and transmit the signal to the nucleus , were also not altered .
Because Raf and MAPK can independently induce nuclear signaling , this suggests that the mechanism of action lies parallel or distal to these secondary messengers .
Lipoxygenase inhibition did result in the suppression of PDGF-induced fos and egr expression .
Collectively , this work suggests that lipoxygenase inhibition leads to the suppression of mitogenesis in part by disrupting the nuclear signaling that is required for protooncogene transcription at a step distal or parallel to MAPK activation .