Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators.
Plasminogen activators are used in thrombolytic stroke therapy. However, it is increasingly recognized that they have other actions besides fibrinolysis. In this study, we assess potential pro-inflammatory effects of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in rat cortical astrocytes. Both uPA and tPA induced rapid dose-dependent upregulation in MMP-2 and MMP-9, as demonstrated by zymography of conditioned media. In addition, a multiplex ELISA array demonstrated that patterned responses in chemokines and cytokines were also evoked. Exposure to tPA induced elevations in secreted MIP-2, MCP-1 and GRO/KC. Exposure to uPA induced elevations in secreted IFN-gamma, TNF-alpha, GMCSF, MIP-1alpha, MIP-2, MIP-3alpha, MCP-1, RANTES and fractalkine. These data suggest that plasminogen activators may trigger selected pro-inflammatory responses at the neurovascular interface. Whether these effects influence thrombolytic stroke therapy warrants further investigation.
Lee
Sun-Ryung
SR
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Guo
Shu-Zhen
SZ
Scannevin
Robert H
RH
Magliaro
Brian C
BC
Rhodes
Kenneth J
KJ
Wang
Xiaoying
X
Lo
Eng H
EH
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism*; D020767:Intracranial Thrombosis / Q000188:drug therapy; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010960:Plasminogen Activators / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9