TGF-beta1 potentiates astrocytic nitric oxide production by expanding the population of astrocytes that express NOS-2.
Both transforming growth factor-beta1 (TGF-beta1) and nitric oxide synthase-2 (NOS-2) are upregulated under various neuropathological states. Evidence suggests that TGF-beta1 can either attenuate or augment NOS-2 expression, with the prevailing effect dependent on the experimental paradigm employed and the cell-type under study. The purpose of the present study was to determine the effect of TGF-beta1 on astrocytic NOS-2 expression. In purified astrocyte cultures, TGF-beta1 alone did not induce NOS-2 or NO production. However, NO production induced by lipopolysaccharide (LPS) plus IFNgamma was enhanced by TGF-beta1 in a concentration-dependent manner between 10 and 1,000 pg/mL. The presence of IFNgamma was not necessary for this effect to occur, as TGF-beta1 enhanced NO production induced by LPS in a similar fashion. In cultures stimulated with LPS plus IFNgamma, the enhancement of NO production by TGF-beta1 was associated with a corresponding increase in NOS-2 mRNA and protein expression. Interestingly, immunocytochemical assessment of NOS-2 protein expression demonstrated that TGF-beta1 augmented astrocytic NO production, specifically by increasing the pool of astrocytes capable of expressing NOS-2 induced by either LPS (approximately threefold) or LPS plus IFNgamma (approximately sevenfold). In a broader sense, our results suggest that TGF-beta1 recruits a latent population of astrocytes to respond to stimulation by pro-inflammatory mediators.
Hamby
Mary E
ME
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Hewett
James A
JA
Hewett
Sandra J
SJ
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004660:Encephalitis / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse