Characterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II

• Published in: The Journal of biological chemistry 1994-10, Vol.269 (40), p.25106-25119
• Main Authors: Kao, J, Houck, K, Fan, Y, Haehnel, I, Libutti, S K, Kayton, M L, Grikscheit, T, Chabot, J, Nowygrod, R, Greenberg, S
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; Cytokines - isolation & purification; Cytokines - pharmacology; Endothelium, Vascular - drug effects; Escherichia coli - chemistry; Female; Humans; Mice; Mice, Inbred C3H; Molecular Sequence Data; Monocytes - drug effects; Neoplasm Proteins - isolation & purification; Neoplasm Proteins - pharmacology; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neutrophils - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(17)31505-3

Endothelial-monocyte activating polypeptide II (EMAP II) was initially identified in the supernatant of murine methylcholanthrene A-induced fibrosarcomas (Meth A) by its capacity to activate host effector cells (Kao, J., Ryan, J., Brett, J., Chen, J., Shen, H., Fan, Y-G., Godman, G., Familletti, P., Wang, F., Pan, Y-C., Stern, D., and Clauss, M. (1992) J. Biol. Chem. 267, 20239-20247). Based on the NH2-terminal protein sequence, a full-length cDNA has been cloned which indicates that the precursor of EMAP II is a unique, leaderless, single polypeptide chain with predicted molecular mass approximately 34 kDa and that the mature form released by Meth A cells corresponds to approximately 20 kDa. Purified recombinant mature EMAP II (EMAP II, approximately 20 kDa form) activated endothelial cells with resulting elevation of cytosolic free calcium concentration, release of von Willebrand factor, induction of tissue factor, and expression of the adhesion molecules E-selectin and P-selectin. Neutrophils exposed to EMAP II demonstrated elevated cytosolic free calcium concentration, peroxidase generation, and chemotaxis. EMAP II also activated mononuclear phagocytes elevating cytosolic free calcium concentration, inducing tumor necrosis factor-alpha (TNF) and tissue factor, and stimulating chemotaxis. Systemic infusion of EMAP II into C3H/HeJ or Balb/c mice was associated with systemic toxicity, pulmonary congestion, and the appearance of TNF, interleukin-1 and -6 in the plasma. A single intra-tumor injection of EMAP II into Meth A sarcomas induced acute thrombohemorrhage and partial tumor regression. Local injection of EMAP II into a tumor resistant to the effects of TNF, murine mammary carcinoma, rendered it sensitive to subsequently administered TNF, which resulted in acute thrombohemorrhage and partial regression. These data suggest that recombinant EMAP II, a tumor-derived cytokine, has properties of a proinflammatory mediator with the capacity to prime the tumor vasculature for a locally destructive process.