title: Albumin activates the canonical TGF receptor-smad signaling pathway but this is not required for activation of astrocytes.
abstract: The use of albumin as a resuscitation fluid is considered safe for most critically ill patients. However, clinical data suggest albumin may increase mortality in neurotrauma, but improve outcome after stroke. Albumin has been shown to activate glia, and to play a role in the mechanisms of epileptogenesis via the TGFβ-receptor (TGFβR). We have previously shown that albumin induces the production of inflammatory mediators including IL-1β via activation of MAPK pathways in primary astrocytes and microglia. The extracellular signaling mechanisms leading to the activation of glial cells in response to albumin are not well understood. Here, we investigated the role of the TGFβR and the canonical TGFβ receptor-smad signaling pathway in astrocyte activation by albumin. In primary astrocyte cultures, albumin activated the smad pathway downstream of the TGFβR by increasing the phosphorylation of smad2, and in the level of smad3 and smad4 translocated to the nucleus. Albumin produced an increase in IL-1β which was not dependent on smad activation, but was prevented by blockade of the TGFβR. Increase in the chemokine CX3CL1, and the decrease in S100B produced by albumin were independent of the TGFβR and smad activation. Albumin induced an increase in LDH release that was inhibited by blockade of the TGFβR and by inhibition of smad activation. These findings show that albumin activates the canonical TGF receptor-smad signaling pathway. The albumin-induced increase in the pro-epileptogenic cytokine IL-1β involves the TGFβR, but is independent of smad activation. Taken together, the effects of albumin on both IL-1β and activation of the TGFβR pathway are further evidence for a role for albumin in neurotrauma-related epileptogenesis.
authors.affiliation: Department of Pediatrics, Division of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL, USA.
authors.forename: Hantamalala
authors.initials: H
authors.lastname: Ralay Ranaivo
authors.forename: Fatima
authors.initials: F
authors.lastname: Patel
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wainwright
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D054360:Chemokine CXCL1 / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000418:Albumins; D001549:Benzamides; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D004149:Dioxoles; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D009573:Nitrites; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D007770:L-Lactate Dehydrogenase; D020929:Mitogen-Activated Protein Kinase Kinases