Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-β1 expression

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 overexprrssion of the active human transforming growth factor-beta1 (ahTGF-beta1) can downregulate expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and intercellular adhesion molecule-1 (ICAM-1) and reduce ischemic brain injury. Methods-Overexpression of transforming growth factor-beta1 (TGF-beta1) 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-beta1, MCP-1, MIP-1 alpha, and ICAM-1 were detected by enzyme-linked immunosorbent assay and immunohistochemistry. Infarct areas and volumes were measured by cresyl violet staining. Results-MCP-1 and MIP-1 alpha 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-beta1 overexpression was significantly greater at measured time points, with a peak at 7 to 9 days. The expression of MCP-1 and MIP-1 alpha, but not ICAM-1, was reduced in the mice overexpressing ahTGF-beta1 (P<0.05). Furthermore, infarct volume was significantly reduced in the mice overexpressing ahTGF-<beta>1 (P<0.05). Conclusions-This study demonstrates that MCP-1 and MIP-1<alpha> expressed in the ischemic region may play an important role in attracting inflammatory cells. The reduction of MCP-1 and MIP-1 alpha, but not ICAM-1, in the mice overexpressing ahTGF-beta1 suggests that the neuroprotective effect of TGF-beta1 may result from the inhibition of chemokines during cerebral ischemia and reperfusion.