| Abstrakt: |
Hemehemopexin supports and stimulates proliferation of human acute T-lymphoblastic (MOLT-3) cells, suggesting the participation of heme in cell growth and division. MOLT-3 cells express approximately 58,000 hemopexin receptors per cell (apparent Kd20 nM), of which about 20% are on the cell surface. Binding is dose- and temperature-dependent, and growth in serum-free IMDM medium is stimulated by 1001000 nMhemehemopexin, consistent with the high affinity of the receptor for hemopexin, and maximal growth is seen in response to 500 nMcomplex. Growth was similar in defined minimal medium supplemented with either low concentrations of hemehemopexin or iron-transferrin, and either of these complexes were about 80% as effective as a serum supplement. Hemehemopexin, but not apohemopexin, reversed the growth inhibition caused by desferrioxamine showing that hemeiron derived from heme catabolism is used for cell growth. Cobalt-protoporphyrin (CoPP)hemopexin, which binds to the receptor but is not transported intracellularly [Smithet al.,(1993)J. Biol. Chem.268, 7365], also stimulated cell proliferation in serum-free IMDM but did not rescue the cells from desferrioxamine. Furthermore, CoPPhemopexin effectively competed for the hemopexin receptor with hemehemopexin and diminished its growth stimulatory effects. In addition, protein kinase C (PKC) is translocated to the plasma membrane within 5 min after hemehemopexin is added to the medium, reaches maximum activity within 510 min, and declines to unstimulated levels by 30 min. Hemehemopexin and CoPP-hemopexin both augmented MOLT-3 cell growth stimulated by serum. Thus, hemehemopexin not only functions as an iron source for T-cells but occupancy of the hemopexin receptor itself triggers signaling pathway(s) involved in the regulation of cell growth. The stimulation of growth of human T-lymphocytes by hemehemopexin is likely to be a physiologically relevant mechanism at sites of injury, infection, and inflammation. |
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