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

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-beta1 and beta2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1beta and TGF-beta mimicked the TIMP-1 downregulation observed with IL-1beta chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-beta combined with IL-1beta increased MMP-2 and decreased proMMP-1 expression compared to IL-1beta 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.

MEK1/2 Inhibitors Block Basal and Transforming Growth Factor β1-Stimulated JC Virus Multiplication

“…There is evidence that TGF-␤1 levels are increased during immunosuppressive conditions, particularly noteworthy in HIV/AIDS (6). Because PML occurs in the context of JCV reactivation during immunosuppression and is most commonly associated with AIDS, our demonstration of JCV stimulation through a TGF-␤1/MEK axis suggests the importance of TGF-␤1 in pathogenesis.…”

Production and Roles of Glial Tissue Inhibitor of Metalloproteinases-1 in Human Immunodeficiency Virus-1-Associated Dementia Neuroinflammation: A Review

“…MMP-7 production by astrocytes, on the other hand, was drastically increased by IL-1beta stimulation after 24 h, but decreased over time to no significant difference to unstimulated cells by day 14 [16] . As for within the first 24 h of stimulation, IL-1beta did not increase astrocyte secretion of MMP-2 unless simultaneously stimulated with TGF-beta1 or TGFbeta2, while the two TGF-beta isoforms significantly downregulated the IL-1beta-stimulated increase of proMMP-1 [5] . Moreover, IL-1beta stimulation significantly upregulated astrocyte secretion of TGFbeta2 after 7 days and TGF-beta1 after 14 days [5] .…”

“…As for within the first 24 h of stimulation, IL-1beta did not increase astrocyte secretion of MMP-2 unless simultaneously stimulated with TGF-beta1 or TGFbeta2, while the two TGF-beta isoforms significantly downregulated the IL-1beta-stimulated increase of proMMP-1 [5] . Moreover, IL-1beta stimulation significantly upregulated astrocyte secretion of TGFbeta2 after 7 days and TGF-beta1 after 14 days [5] . These studies demonstrated the intricate network of inflammatory cytokine signaling and feedback to astrocytes and the inherent differences in expression patterns of different MMPs in astrocytes.…”

“…Expression of MMPs and TIMP-1 is known to be regulated by inflammatory cytokines [4] , which are in turn differentially expressed in neuroinflammation. Compared to healthy controls, both HIV+ and HIVE brain samples exhibited significantly higher mRNA levels for IL-1beta [3] and higher protein levels of TGF-beta2, while TGF-beta2 mRNA was significantly increased only in HIVE samples [5] . TIMP-1 protein levels, however, were significantly lower in both HIVE and HIV+ patients as compared to healthy controls [3] .…”

“…[7] . MMPs are classified according to the type of substrates: MMP-2 and -9 are the prominent gelatinases, MMP-1 is the most well-studied of the collagenases and other types of MMPs include stromelysins (e.g., MMP-3), matrilysins (e.g., MMP-7) and Membrane-Type (MT)-MMPs which are attached to the outer surface of cell membranes rather than soluble in the extracellular milieu [5] . MMPs are also responsible for processing cell-surface signaling receptors and their ligands, such as the apoptosisinducing Fas Ligand (FasL) [7] .…”