Increased Expression of Transforming Growth Factor-β after Cerebral Ischemia in the Baboon: An Endogenous Marker of Neuronal Stress?

Abstract

There has been an increasing interest in recent years in the evaluation of the neuronal and glial responses to ischemic insult. Some cytokines, including transforming growth factor-beta (TGF-beta), that are overexpressed after experimental stroke in rodents are thought to be implicated in the neuronal processes that lead to necrosis. Thus, such cytokines could predict tissue fate after stroke in humans, although data are currently sparse for gyrencephalic species. The current study addressed the expression pattern of TGF-beta1 in a nonhuman primate model of middle cerebral artery occlusion. Focal permanent ischemia was induced for 1 or 7 days in 6 baboons and the following investigations were undertaken: cerebral oxygen metabolism (CMRO2) positron emission tomography studies, magnetic resonance imaging, postmortem histology, and reverse transcription-polymerase chain reaction. The aim of the current study was to correlate the expression of TGF-beta1 to the underlying metabolic and histologic state of the threatened cerebral parenchyma. The authors evidenced increased TGF-beta1 mRNA levels (up to 25-fold) in those regions displaying a moderate (20% to 49%) reduction in CMRO2. The current findings suggest that the greatly enhanced expression of TGF-beta1 in the penumbral zones that surround tissue destined to infarction may represent a robust index of potentially salvageable brain. The current investigation, in the nonhuman primate, strengthens the authors' hypothesis, derived from rodent models, that TGF-beta1 may be involved in the physiopathology of human stroke.

Matching Gene Expression with Hypometabolism after Cerebral Ischemia in the Nonhuman Primate

“…Interestingly, in our study, we confirm the overexpression of genes such as IL-1ß, TNF-␣, TGF-ß1, VEGF receptor, MCP-1, MIP-1␣, and heat-shock protein (hsp)-70 in injured tissue, compared with healthy contralateral areas. The results obtained with the expression pattern of TGF-ß1 based on the present microarray technique are in agreement with our previous data in the same model of cerebral ischemia in the baboon, when estimated by either RT-PCR or immunoblotting (Ali et al, 2001). The present study confirms that the microarray analysis is a powerful tool for the identification of differential gene expression in experimental stroke and thus the development of potential therapeutic targets.…”

The immunologic profile of adoptively transferred lymphocytes influences stroke outcome of recipients

“…Systemic IL-6 increases within hours after stroke onset (Beamer et al, 1995; Waje-Andreassen et al, 2005). There is also rapid upregulation of IL-6 and TGF-β1 expression in ischemic brain (Krupinski et al, 1996; Suzuki et al, 1999; Legos et al, 2000; Ali et al, 2001). The cytokines necessary for the development of a Th17 response are thus usually present after stroke.…”

Astrocytes as a Source for Extracellular Matrix Molecules and Cytokines

“…The cytokine TGF-β1 is generally expressed at low to undetectable levels in the brain, but it is strongly up regulated under neuropathological conditions in various neurologic diseases (Kiefer et al, 1993a,b, 1995; Morgan et al, 1993; Wang et al, 1995; Peress et al, 1996; Vawter et al, 1996; Ata et al, 1997; Krupinski et al, 1998; De Groot et al, 1999; Ali et al, 2001; Zetterberg et al, 2004). TGF-β1 signals by binding to TGFβRII.…”