Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1...

Background and Purpose-Chemokines have been shown to play an important role in leukocyte and monocyte/macrophage infiltration into ischemic regions. The purpose of this study is to identify whether overexpression of the active human transforming growth factor-ss1 (ahTGF-ss1) can downregulate expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and intercellular adhesion molecule-1 (ICAM-1) and reduce ischemic brain injury.

-Overexpression of transforming growth factor-ss1 (TGF-ss1) was achieved through adenoviral gene transfer. Five days after adenoviral transduction, the mouse underwent 30 minutes of middle cerebral artery occlusion followed by 1 to 7 days of reperfusion. TGF-ss1, MCP-1, MIP-1alpha, and ICAM-1 were detected by enzyme-linked immunosorbent assay and immunohistochemistry. Infarct areas and volumes were measured by cresyl violet staining.

-MCP-1 and MIP-1alpha expression is increased after middle cerebral artery occlusion, and double-labeled immunostaining revealed that MCP-1 is colocalized with neurons and astrocytes. Viral-mediated TGF-ss1 overexpression was significantly greater at measured time points, with a peak at 7 to 9 days. The expression of MCP-1 and MIP-1alpha, but not ICAM-1, was reduced in the mice overexpressing ahTGF-ss1 (P:<0.05). Furthermore, infarct volume was significantly reduced in the mice overexpressing ahTGF-ss1 (P:<0.05).

-This study demonstrates that MCP-1 and MIP-1alpha expressed in the ischemic region may play an important role in attracting inflammatory cells. The reduction of MCP-1 and MIP-1alpha, but not ICAM-1, in the mice overexpressing ahTGF-ss1 suggests that the neuroprotective effect of TGF-ss1 may result from the inhibition of chemokines during cerebral ischemia and reperfusion.