Regulation of EMAP II by Hypoxia

Abstract

Endothelial-monocyte-activating polypeptide II (EMAP II) is a proinflammatory cytokine and a chemoattractant for monocytes and granulocytes. We have previously shown that EMAP II mRNA is strongly expressed at sites of apoptosis in the mouse embryo and that the mature protein is cleaved from its cellular precursor (proEMAP II/p43) by caspase activation to become released from cells. Here we demonstrate in vivo that EMAP II mRNA expression is strongly increased in tumor necrosis factor alpha (TNF)-treated murine meth A fibrosarcomas and in B16 melanomas, especially in close proximity to areas of tissue necrosis. Furthermore, by means of confocal microscopy, high level expression of proEMAP II/p43 protein correlated predominantly with hypoxic but also with apoptotic cells. In vitro, EMAP II mRNA levels were not increased by hypoxia. However, high amounts of mature EMAP II protein were detected in the supernatants of hypoxic tumor cells. Unlike in apoptotic cells, neither a broad-range caspase inhibitor nor an inhibitor specific for the internal cleavage site was able to inhibit processing of proEMAP II/p43 to the mature EMAP II protein. In conclusion, these data suggest that hypoxia and apoptosis provide two alternative mechanisms of EMAP II generation by tumor cells.

The impact of hypoxia on tumor-associated macrophages

“…Hypoxia induces the expression of VEGF, EMAP-II, endothelin, SEMA3A, SDF1α, eotaxin, and oncosatin M, thus explaining the enhanced availability of these factors within oxygen-deprived regions (19,(44)(45)(46)(47)(48)(49). The cytokine-rich tumor microenvironment further provides factors such as CCL2, CCL5, or CSF1 produced by many different cell types such as tumor cells, fibroblasts, endothelial cells, or TAMs themselves (43).…”

AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability

“…In the cytoplasm, AIMP1 helps the catalytic reaction of arginyl-tRNA synthetase. Recently, it has been demonstrated that AIMP1 is secreted as a result of various stimuli, including TNF-␣, heat shock, and hypoxia (13)(14)(15), and that it acts as a multifunctional cytokine on both endothelial and immune cells (16 -19). …”

Macrophage migration and gene expression in response to tumor hypoxia

“…It appears that TAMs may be recruited to these hypoxic sites by the release of macrophage chemoattractants by hypoxic tumor and other stromal cells. These include VEGF, 25 endothelin-2 26 and EMAPII, 27 which are upregulated by hypoxic tumor cells. It is also likely that, as TAMs are phagocytic scavenger cells, they will be attracted by signals released by apoptotic tumor cells, cell debris from necrosis, or constituents released by the local extracellular matrix (ECM) as tumor cells undergo necrosis.…”