Arachidonic acid lipoxygenation may mediate interleukin-1 stimulation of nerve growth factor secretion in astroglial cultures.
Interleukin-1 beta (IL-1) stimulates by about fivefold NGF secretion from rat neonatal cortical astrocytes in primary culture. We investigated the possible intracellular second messenger mechanisms involved in the IL-1 induced NGF secretion. Basal NGF secretion did not require extracellular Ca2+, whereas Ca2+ was necessary for the maximal NGF secretion stimulated by IL-1 (10 units/ml). The protein kinase C activator TPA stimulated by sixfold NGF secretion, but in this case, TPA acted synergistically with IL-1 to increase NGF secretion. Treatment of cells with the phospholipase A2 inhibitor mepacrine (30 microM) inhibited basal (by 50%) and IL-1 stimulated (by 80%) NGF secretion. Indomethacin, a cyclooxygenase inhibitor, produced a slight increase in basal NGF secretion at low concentrations, while PGE2 (10 microM) inhibited basal and IL-1 stimulated NGF secretion. In contrast, treatment of cells with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, blocked in a concentration-dependent manner (IC50 = 10 microM) IL-1 stimulation of NGF secretion. The leukotriene LTB4 increased basal NGF secretion and this effect was not additive with IL-1 when both agents were added at saturating concentrations, indicating a common mechanism of action for these two agents. Thus, one possible mechanism by which IL-1 stimulates NGF secretion from astrocytes is by activation of the phospholipase A2-lipoxygenase pathway.
Carman-Krzan
M
M
Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical School, Washington, D.C. 20007.
Wise
B C
BC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D050356:Lipid Metabolism; D008084:Lipoxygenase / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism*; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical
D007375:Interleukin-1; D009414:Nerve Growth Factors; D016718:Arachidonic Acid; D009637:Masoprocol; D008084:Lipoxygenase; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium; D007213:Indomethacin