Novel role of TGF‐β in differential astrocyte‐TIMP‐1 regulation: Implications for HIV‐1‐dementia and neuroinflammation

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Abstract
Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)‐1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV‐1‐associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP‐1 in the brain. Astrocyte‐TIMP‐1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006 ), we investigate the mechanisms that may be involved in differential TIMP‐1 regulation. One mechanism for TIMP‐1 downregulation is the production of anti‐inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)‐signaling in astrocyte‐MMP/TIMP‐1‐astrocyte regulation. TGF‐β1 and β2 levels were upregulated in HAD brain tissues. Co‐stimulation of astrocytes with IL‐1β and TGF‐β mimicked the TIMP‐1 downregulation observed with IL‐1β chronic activation. Measurement of astrocyte‐MMP protein levels showed that TGF‐β combined with IL‐1β increased MMP‐2 and decreased proMMP‐1 expression compared to IL‐1β alone. We propose that one of the mechanisms involved in TIMP‐1 downregulation may be through TGF‐signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte‐TIMP‐1 regulation.