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Response to Comment on "Cutting Edge: Extracellular High Mobility Group Box-1 Protein Is a Proangiogenic Cytokine"

General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia Brescia, Italy

The possibility that thrombomodulin (TM) may inhibit the proangiogenic activity of high mobility group box 1 protein (HMGB1) is intriguing. TM is an endothelial cell-membrane glycoprotein (1). It consists of five distinct domains: an N-terminal lectin-like region (D1); a region consisting of six epidermal growth factor-like structures (D2); an O-glycosylated domain (D3); a transmembrane region (D4); and a cytoplasmic tail (D5) (2).

D2 is critical for the anticoagulant activity of TM, whereas D1 is endowed with anti-inflammatory properties and mediates cell-to-cell adhesion. Recently, D1 has been demonstrated to bind HMGB1 and to blunt its RAGE-mediated proinflammatory activity (3). Therefore, it is conceivable that TM may also affect the RAGE-mediated proangiogenic activity of HMGB1. On the other hand, recent observations have shown that a recombinant peptide spanning the D2-D3 domains of TM exerts a significant angiogenic activity in vitro and in vivo (4). Interestingly, proteolytic cleavage products of various molecules have been shown to exert opposing effects on angiogenesis (e.g. antiangiogenic tumstatin and endostatin or proangiogenic angiogenin) (5).

Taken together, these observations suggest that TM may act as a modular protein with multifunctional potential in affecting endothelial cell responses during inflammation.

TM expression levels, extracellular TM shedding and proteolytic processing, and engagement by thrombin (another angiogenesis mediator) may all affect TM-HMGB1 interaction and the angiogenic balance. Even though further experimental work will be required to assess this hypothesis, the data emphasize the tight crosstalk between angiogenesis and inflammation.

References

1. Esmon, C. T., W. G. Owen. 2004. The discovery of thrombomodulin. J. Thromb. Haemost. 2: 209-213. [Medline]
2. Dittman, W. A., P. W. Majerus. 1990. Structure and function of thrombomodulin: a natural anticoagulant. Blood 75: 329-336. [Free Full Text]
3. Abeyama, K., D. M. Stern, Y. Ito, K. Kawahara, Y. Yoshimoto, M. Tanaka, T. Uchimura, N. Ida, Y. Yamazaki, S. Yamada, et al 2005. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115: 1267-1274. [Medline]
4. Shi, C. S., G. Y. Shi, Y. S. Chang, H. S. Han, C. H. Kuo, C. Liu, H. C. Huang, Y. J. Chang, P. S. Chen, H. L. Wu. 2005. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 111: 1627-1636. [Abstract/Free Full Text]
5. Wickstrom, S. A., K. Alitalo, J. Keski-Oja. 2005. Endostatin signaling and regulation of endothelial cell-matrix interactions. Adv. Cancer Res. 94: 197-229. [Medline]

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