Regulation of endothelial cell (EC) coagulant, barrier, adhesive and proliferative functions is central to inflammation, and the host response to tumors. We have identified, cloned and characterized a novel polypeptide, designated Endothelial-Monocyte Activating Polypeptide II (EMAPII), which modulates these EC functions, and is phlogogenic and angiogenic. EMAPII is synthesized by activated murine mononuclear phagocytes (MPs) and constitutively by murine Meth A sarcoma (Meth A) cells, and is secreted as an about 18-20 kDA single chain molecule. EMAPII also activates both MPs, stimulating cell migration and tissue factor synthesis, and polymorphonuclear leukocytes (PMNs), promoting chemotaxis and superoxide generation. In vivo, subcutaneously administered EMAPII elicits inflammation; but Meth A tumor cells transfected to constitutively overexpress EMAPII exhibit increased growth. We hypothesize that the context and kinetics of EMAPII production determine its biologic properties, either as phlogogenic agent in inflammatory settings, or as inducer of neoangiogenesis in tumors.
The specific aims are to understand mechanisms by which EMAPII elicits inflammation, and influences tumor-host reactions. Using cDNA probes and antibodies to EMAPII (murine and human), we will identify sites of synthesis and accumulation in a spectrum of tumors, inflammatory and vascular lesions. Functional activity of a region of mature EMAPII near the HN2-terminus, which, in synthetic peptides, stimulates PMN and MP migration, binds specifically to cells, and cross-links to an about 73 kDa cell surface polypeptide will be examined using additional peptides and site-directed mutagenesis. These reagents will also be used to characterize and isolate the EMAPII cell surface binding site. Based on strong sequence homology between the NH2-terminal region of EMAPII and von Willebrand antigen II (vWAgII, a polypeptide in platelet alpha- granules and released by stimulated ECs), we have shown that vWAgII has properties resembling EMAPII. Because of the role of secreted platelet proteins in tissue repair, we will assess the effects of vWAgII on ECs, MPs, and PMNs, and determine its contribution to inflammation and wound repair in animal models. And since elevated levels of vWAgII, consequent on infusion of the arginine vasopressin analog, DDAVP, induced MP tissue factor, we will find out whether vWAgII is capable of initiating activation of procoagulant mechanisms in vivo, and the thrombosis complicating DDAVP therapy. These studies offer new means of linking coagulation with inflammation, and define a new ligand-receptor interaction, involving EMAPII, relevant to host responses in inflammation, neoplasia and, vasculopathies, such as atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL042833-06
Application #
2220710
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-03-01
Project End
1998-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Schwarz, M A; Kandel, J; Brett, J et al. (1999) Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells. J Exp Med 190:341-54
Niitsu, Y; Hori, O; Yamaguchi, A et al. (1999) Exposure of cultured primary rat astrocytes to hypoxia results in intracellular glucose depletion and induction of glycolytic enzymes. Brain Res Mol Brain Res 74:26-34
Bohrer, H; Qiu, F; Zimmermann, T et al. (1997) Role of NFkappaB in the mortality of sepsis. J Clin Invest 100:972-85
Zhang, Y; Deng, Y; Wendt, T et al. (1996) Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor-induced tissue factor expression and fibrin deposition in mouse meth-A sarcoma. J Clin Invest 97:2213-24
Hori, O; Matsumoto, M; Kuwabara, K et al. (1996) Exposure of astrocytes to hypoxia/reoxygenation enhances expression of glucose-regulated protein 78 facilitating astrocyte release of the neuroprotective cytokine interleukin 6. J Neurochem 66:973-9
Hori, O; Yan, S D; Ogawa, S et al. (1996) The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus. Nephrol Dial Transplant 11 Suppl 5:13-6
Marvin, M R; Libutti, S K; Kayton, M et al. (1996) A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor. J Surg Res 63:248-55
Lawson, C A; Smerling, A J; Naka, Y et al. (1995) Selective reduction of PVR by inhalation of a cGMP analogue in a porcine model of pulmonary hypertension. Am J Physiol 268:H2056-62
Yellin, M J; Brett, J; Baum, D et al. (1995) Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals. J Exp Med 182:1857-64
Yuzawa, Y; Brett, J; Fukatsu, A et al. (1995) Interaction of antibody with Forssman antigen in guinea pigs. A mechanism of adaptation to antibody- and complement-mediated injury. Am J Pathol 146:1260-72

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