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Thromb Haemost 2004; 92(04): 811-819
DOI: 10.1160/TH04-03-0188
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation

Ellinor I. B. Peerschke
1   Department of Pathology,Weill Medical College of Cornell University; New York, USA
,
Ramona J. Petrovan
2   Department of Immunology,The Scripps Research Institute, La Jolla, California, USA
,
Berhane Ghebrehiwet
3   Department of Medicine, Stony Brook University, Stony Brook, New York, USA
,
Wolfram Ruf
2   Department of Immunology,The Scripps Research Institute, La Jolla, California, USA
› Author AffiliationsFinancial support: Supported in part by grants NIH NHLBI 67211 (EIBP, BGH), RPG-95068-06 from the American Cancer Society (B.G.), and a generous gift from Larry and Sheila Dalzell.
Further Information

Publication History

Received 25 March 2004

Accepted after resubmission 27 July 2004

Publication Date:
06 December 2017 (online)

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Summary

Evidence is accumulating to suggest that TFPI-2 is involved in regulating pericellular proteases implicated in a variety of physiologic and pathologic processes including cancer cell invasion, vascular inflammation, and atherosclerosis. Recent immunohistochemical studies of advanced atherosclerotic lesions, demonstrated a similar tissue distribution for TFPI-2, High Molecular Weight Kininogen (HK), and gC1qR/p33 (gC1qR), a ubiquitously expressed, multicompartmental cellular protein involved in modulating complement, coagulation, and kinin cascades. Further studies to evaluate TFPI-2 interactions with gC1qR demonstrated direct interactions between gC1qR and TFPI-2 using immunoprecipitation and solid phase binding studies. Specific and saturable binding between TFPI-2 and gC1qR (estimated Kd: ∼ 70 nM) was observed by ELISA and surface plasmon resonance (Biacore) binding assays. Binding was inhibited by antibodies to gC1qR, and was strongly dependent on the Kunitz-2 domain of TFPI-2, as deletion of this domain reduced gC1qR-TFPI-2 interactions by approximately 75%. Deletion of gC1qR amino acids 74-95, involved in C1q binding, had no effect on gC1qR binding to TFPI-2, although antibodies to this region and purified C1q both inhibited binding, most likely via allosteric effects. In contrast, HK did not affect TFPI-2 binding to gC1qR. Binding of TFPI-2 to gC1qR produced statistically significant but modest reductions in TFPI-2 inhibition of plasmin, but had no effect on kallikrein inhibition in fluid phase chromogenic assays. Taken together, these data suggest that gC1qR may participate in tissue remodeling and inflammation by localizing TFPI-2 to the pericellular environment to modulate local protease activity and regulate HK activation.

Keywords

Fibrinolysis inhibitors - proteases / inhibitors - proteolysis / pericellular - tissue factor pathway inhibitor (TFPI) - atherosclerosis
 

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