Premium
Autocrine enhancement of leukotriene synthesis by endogenous leukotriene B 4 and platelet‐activating factor in human neutrophils
Author(s) -
McDonald Patrick P.,
McColl Shaun R.,
Braquet Pierre,
Borgeat Pierre
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14816.x
Subject(s) - leukotriene b4 , leukotriene , platelet activating factor , endogeny , leukotriene d4 , autocrine signalling , chemistry , platelet , leukotriene c4 , endocrinology , medicine , receptor , inflammation , biochemistry , asthma
1 Platelet‐activating factor (PAF) and leukotriene B 4 (LTB 4 ), two potent lipid mediators synthesized by activated neutrophils, are known to stimulate several neutrophil functional responses. In this study, we have determined that endogenous LTB 4 and PAF exert autocrine effects on LT synthesis, as well as the underlying mechanism involved. 2 Pretreatment of neutrophils with either pertussis toxin (PT), or with receptor antagonists for LTB 4 and PAF, resulted in an inhibition of LT synthesis induced by calcium ionophore, A23187. This inhibition was most marked at submaximal (100– 300 n m ) A23187 concentrations, whilst it was least at ionophore concentrations which induce maximal LT synthesis (1–3 μ m ). Thus newly‐synthesized PAF and LTB 4 can enhance LT synthesis induced by A23187 under conditions where the LT‐generating system is not fully activated. 3 In recombinant human (rh) granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐primed neutrophils, LT synthesis in response to chemoattractants (fMet‐Leu‐Phe or rhC5a) was also significantly inhibited by the LTB 4 receptor antagonist, and to a lesser extent by PAF receptor antagonists. 4 Further investigation revealed that LTB 4 and/or PAF exert their effects on LT synthesis via an effect on arachidonic acid (AA) availability, as opposed to 5‐lipoxygenase (5‐LO) activation. Indeed, the receptor antagonists, as well as PT, inhibited LT synthesis and AA release to a similar extent, whereas 5‐LO activation (assessed with an exogenous 5‐LO substrate) was virtually unaffected under the same conditions. Accordingly, we showed that addition of exogenous LTB 4 could enhance AA availability in response to chemoattractant challenge in rhGM‐CSF‐primed cells, without significantly affecting the 5‐LO activation status. 5 Our data show that newly‐generated PAF and LTB 4 have the ability to positively feedback on LT synthesis by acting at the level of the phospholipase A 2 /re‐esterification component of the LT biosynthetic pathway in neutrophils. Such autocrine affects are likely to represent an important amplification step of LT synthesis, and may as such contribute to the rapid onset, as well as to the evolution, of inflammatory responses.