Opposite regulation of prostaglandin E2 synthesis by transforming growth factor-beta1 and interleukin 10 in activated microglial cultures.
We have recently shown that prostaglandin E2 (PGE2) synthesis in activated microglia is tightly regulated by several substances (NO, neurotransmitters, pro-inflammatory cytokines), that might originate from intrinsic brain cells or from hematogenous cells infiltrating the brain in the course of inflammatory diseases. In view of the important immunoregulatory and neuroprotective functions recently attributed to PGE2, in the present study we extended our analysis of factors regulating PGE2 synthesis in rat microglial cultures to two anti-inflammatory and immunosuppressive cytokines, transforming growth factor beta1 (TGF-beta1) and interleukin 10 (IL-10), which share with PGE2 the ability to strongly deactivate peripheral macrophages and microglial cells. Moreover, we looked at the effect of the two cytokines on nitric oxide (NO) synthesis, another important microglial effector, whose synthesis is linked to that of PGE2 by complex feed-back mechanisms. We found that while both cytokines inhibited LPS-induced NO release, they had distinct and opposite regulatory activities on PGE2 production. In fact, while TGF-beta1 enhanced LPS-induced PGE2 synthesis, IL-10 showed an inhibitory effect. The two cytokines acted mainly by regulating the LPS-induced expression of the rate limiting enzymes of the two metabolic pathways, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS). Moreover, TGF-beta1 counteracted the effect of the pro-inflammatory cytokine interferon-gamma, which in the same cultures has been shown to downregulate PGE2 and to upregulate NO synthesis. Although the present in vitro observations cannot be directly extrapolated to the in vivo situation, they may provide a novel clue for understanding the specific role of TGF-beta1 and IL-10 in several neurological diseases such as multiple sclerosis, in which their cerebral level was found to be elevated.
Minghetti
Luisa
L
Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Polazzi
Elisabetta
E
Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Nicolini
Alessia
A
Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Levi
Giulio
G
Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000494:pharmacology; D010544:Peroxidases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009573:Nitrites; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D010544:Peroxidases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone