In situ assays demonstrate that interferon-gamma suppresses infection-stimulated hepatic fibrin deposition by promoting fibrinolysis.
J Thromb Haemost
; 4(7): 1580-7, 2006 Jul.
Article
in En
| MEDLINE
| ID: mdl-16839357
ABSTRACT
BACKGROUND:
Inflammatory cytokines potently impact hemostatic pathways during infection, but the tissue-specific regulation of coagulation and fibrinolysis complicates studies of the underlying mechanisms. METHODS ANDRESULTS:
Here, we describe assays that quantitatively measuring prothrombinase (PTase), protein C-ase (PCase) and plasminogen activator (PA) activities in situ, thereby facilitating studies of tissue-specific hemostasis. Using these assays, we investigate the mechanisms regulating hepatic fibrin deposition during murine toxoplasmosis and the means by which interferon-gamma (IFN-gamma) suppresses infection-stimulated fibrin deposition. We demonstrate that Toxoplasma infection upregulates hepatic PTase, PCase, and PA activity. Wild type and gene-targeted IFN-gamma-deficient mice exhibit similar levels of infection-stimulated PTase activity. By contrast, IFN-gamma-deficiency is associated with increased PCase activity and reduced PA activity during infection. Parallel analyses of hepatic gene expression reveal that IFN-gamma-deficiency is associated with increased expression of thrombomodulin (TM), a key component of the PCase, increased expression of thrombin-activatable fibrinolysis inhibitor (TAFI), a PC substrate, and reduced expression of urokinase PA (u-PA).CONCLUSIONS:
These findings suggest that IFN-gamma suppresses infection-stimulated hepatic fibrin deposition by suppressing TM-mediated activation of TAFI, thereby destabilizing fibrin deposits, and concomitantly increasing hepatic u-PA activity, thereby promoting fibrinolysis. We anticipate that further application of these in situ assays will improve our understanding of tissue-specific hemostasis, its regulation by cytokines, and its dysregulation during coagulopathy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fibrin
/
Interferon-gamma
/
Fibrinolysis
/
Infections
/
Liver
Limits:
Animals
Language:
En
Journal:
J Thromb Haemost
Journal subject:
HEMATOLOGIA
Year:
2006
Type:
Article
Affiliation country:
United States