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.