EMAP II: A Cytokine Regulated By Apoptosis

November 06, 1998

Endothelial monocyte-activating polypeptide II (EMAP II) is a proinflammatory cytokine and a chemoattractant for monocytes. Scientists at the Max Planck Institute for Physiological and Clinical Research (Bad Nauheim, Germany) have demonstrated a regulatory role for apoptosis in the processing of the EMAP II precursor to the biologically active form, implicating EMAP II in the attraction of monocytes to sites of apoptosis.

Endothelial monocyte-activating polypeptide II (EMAP II) was originally purified from supernatants of Meth A fibrosarcoma cells due to its ability to induce tissue factor, the initiator of coagulation, on endothelial cells. EMAP II has been characterised as a proinflammatory cytokine capable of stimulating the chemotactic migration of monocytes and neutrophils as well as of activating endothelial cells and monocytes to become macrophages. In vivo, injection of EMAP II into the mouse footpad results in an inflammatory swelling response characterised by a cellular infiltrate and edema. Cloning of the EMAP II-cDNA revealed that EMAP II is translated as a precursor protein which is processed to become the biologically active mature form that is subsequently released from the cell. Since both the human and the mouse EMAP II precursor proteins are cleaved after an aspartic acid residue, the EMAP II cleavage site resembles target sites of caspases, a family of proteases with a pivotal role in apoptosis, also known as programmed cell death.

Little was known about the expression of EMAP II or the regulation of its cleavage. Scientists in W. Risau’s department at the Max Planck Institute for Clinical and Physiological Research in Bad Nauheim have analyzed the expression pattern of the EMAP II gene during embryogenesis of the mouse and found that the EMAP II messenger-RNA (mRNA) is predominantly expressed at sites of tissue remodelling. Since it is known that programmed cell death is a necessary requirement for tissue remodelling, mouse embryos were analyzed for the presence of apoptotic cells. A high rate of apoptosis was detected in tissues with a strong EMAP II mRNA expression. The removal of dead cells during apoptosis requires macrophages and an accumulation of macrophages in areas of EMAP II expression and apoptosis could be observed.

As the expression pattern of EMAP II during mouse development suggested a role for programmed cell death in the regulation of EMAP II, the effect of apoptosis on the posttranslational processing of the EMAP II precursor protein was investigated in vitro. It could be shown that following the induction of apoptosis, the EMAP II precursor protein was cleaved and the mature EMAP II released from the cell, whereas the induction of necrotic cell death had no effect on the processing of the EMAP II precursor. The release of mature EMAP II following the induction of apoptosis could be abrogated by a specific tetrapeptide inhibitor which competes with the cleavage site of the EMAP II precursor. Further experiments using other peptide inhibitors indicated that EMAP II is cleaved by a caspase-like enzyme.

This study demonstrates that, during embryonic development, the EMAP II mRNA colocalizes with sites of programmed cell death and that the posttranslational processing of the EMAP II precursor is induced by apoptosis. Since the mature EMAP II is a chemoattractant for macrophages, its release following apoptosis suggests that EMAP II recruits macrophages to sites of apoptosis. So far, no other mechanism has been described which can explain the accumulaion of macrophages at sites of cell death during embryonic development. Taken together, these results imply that the coordinate program of cell death includes activation of a capase-like activity that initiates the processing of a cytokine responsible for macrophage attraction to the sites of apoptosis.
Original paper:
Knies, U. E., Behrensdorf, H. A., Mitchell, C. A., Deutsch, U., Risau, W., Drexler, H. C. A. and Clauss, M.: Regulation of endothelial monocyte-activating polypeptide II release by apoptosis. PNAS 95 (21): 12322 - 12327 (1998).


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