Novel role of TGF-beta in differential astrocyte-TIMP-1 regulation: implications for HIV-1-dementia and neuroinflammation.
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.
Laboratory of Cellular Neuroimmunology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Alok
A
Dhar
Jessica
J
Gardner
Kathleen
K
Borgmann
Li
L
Wu
Anuja
A
Ghorpade
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000503:physiopathology; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D004792:Enzyme Precursors; D007375:Interleukin-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D017364:Collagenases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1