Gonadotropin releasing hormone activates the lipoxygenase pathway in cultured pituitary cells: role in gonadotropin secretion and evidence for a novel autocrine/paracrine loop.
The formation and role of arachidonic acid (AA) and its metabolites during gonadotropin releasing hormone- (GnRH-) induced gonadotropin secretion were investigated in primary cultures of rat pituitary cells. Prelabeled cells ([3H]AA) responded to GnRH challenge with increased formation (about 2-fold) of the leukotrienes LTC4, LTD4, and LTE4 as well as 5- and 15-eicosatetraenoic acids (5- and 15-HETE) as identified by HPLC. Formation of leukotrienes and 15-HETE was further verified by specific radioimmunoassays. No significant increase in the formation of 12-HETE or of the cyclooxygenase products prostaglandin E (PGE) and thromboxane A2 by GnRH was noticed. Addition of physiological concentrations of LTC4 enhanced basal LH release, while subphysiological concentrations of LTC4 (10(-15)-10(-12) M) inhibited GnRH-induced LH release by about 35% (p less than 0.02). Using specific lipoxygenase inhibitors L-656,224 and MK 886, we found inhibition of GnRH-induced LH release by about 40% at concentrations known to specifically inhibit the 5-lipoxygenase pathway. The peptidoleukotriene receptor antagonist ICI 198,615 inhibited LTC4- and LTE4-induced LH release and surprisingly also the effect of GnRH on LH release by 40%. The data strongly suggest a role for AA and its lipoxygenase metabolites in the on/off reactions of GnRH upon LH release. The data also present a novel amplification cycle in which newly formed leukotrienes become first messengers and establish an autocrine/paracrine loop.
Dan-Cohen
H
H
Department of Biochemistry, Tel Aviv University, Israel.
Sofer
Y
Y
Schwartzman
M L
ML
Natarajan
R D
RD
Nadler
J L
JL
Naor
Z
Z
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D015777:Eicosanoids / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism; D010902:Pituitary Gland / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D015290:Second Messenger Systems; D012636:Secretory Rate / Q000187:drug effects; D015398:Signal Transduction
D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D007191:Indazoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C054217:ICI 198615; D016718:Arachidonic Acid; D007987:Gonadotropin-Releasing Hormone; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D007986:Luteinizing Hormone; D008084:Lipoxygenase