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Title: DIFFERENTIATION OF HUMAN U937 PROMONOCYTIC CELLS IS IMPAIRED BY MODERATE COPPER DEFICIENCY

Author
item HUANG, ZHIXIN - UNIV OF NORTH CAROLINA
item FAILLA, MARK - UNIV OF NORTH CAROLINA
item Reeves, Phillip

Submitted to: Society For Experimental Biology And Medicine Proceedings
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/1/2000
Publication Date: 3/1/2001
Citation: Huang, Z.L., Failla, M.L., Reeves, P.G. 2001. Differentiation of human U937 promonocytic cells is impaired by moderate copper deficiency. Experimental Biology and Medicine. 226(3):222-228.

Interpretive Summary: Copper is an essential trace element for many biochemical processes of the body. Humans or animals that consume low daily amounts of copper in their diets develop deficiency signs that result in diminished health and well-being. The immune system of the body is one of the processes that copper affects. Part of the immune response to various types of infection involves white blood cells called monocytes. When the body is attacked, some of the white cells go through a biochemical change to fight the infection. This change process is called differentiation. In previous work, the infection fighting ability of these cells was reduced in copper deficient animals. To get a better idea of how copper deficiency is affecting the cell, the current research looked at the roles of copper in monocyte differentiation and bacterial killing responses. Immature monocytes were grown in culture in the presence of a compound called 2,3,2-tetraamine (Tet) that binds copper and causes the cell to become copper deficient. Because of this treatment, the concentration of copper in the cell decreased by 55%, but there was no effect on other cell trace elements such as zinc and iron. In addition, the cells with low copper failed to differentiate properly and lost their ability to kill bacteria. However, the treatment with Tet was mild enough so that other copper- requiring functions such as superoxide dismutase activity, a marker for copper deficiency, were not affected. When sufficient copper was given back to the cells, the failed responses were reversed. This research demonstrates that copper is essential for monocyte differentiation processes and that copper contributes to the ability of the body to fight off infections.

Technical Abstract: Dietary copper (Cu) deficiency suppresses the macrophage activities in host defense. Our previous studies indicated that the induction of Cu deficienc in the differentiated U937 monocytic cells impairs respiratory burst and bactericidal activities and lipopolysaccharide-mediated secretion of inflammatory mediators. The current investigation examined the roles of Cu uthe monocytic differentiation process. Human U937 promonocytic cells were exposed to 5 uM 2,3,2-tetraamine (tet), a high affinity Cu chelator, for 24 to selectively lower cellular Cu status. The presence of tet during the subsequent 48-h differentiation of the moderate Cu deficient cells by 10 nM 1,25-dihydroxyvitamin D3 plus 5 ng interferon-gamma/ml (DI) decreased cell by 55% without compromising cellular Zn, Fe and metabolic activity. Lower status significantly attenuated the expression of maturation markers Mac-1 (CD11b), ICAM-1 (CD54) and LPS-R (CD14). The suboptimal differentiation wa aassociated with a marked suppression in respiratory burst activity and kil of Salmonella. To examine if the adverse effect of inadequate Cu on the DI induced differentiation represented a more general defect, U937 cells were exposed to 10 nM phorbol 12-myristate 13-acetate (PMA). Lower Cu status caused the same types of suppression in the PMA-differentiated cells. Supplemental Cu, but not Zn or Fe, blocked the tet-induced declines in cell Cu, expression of maturation markers, and respiratory burst and bactericida activities. These results demonstrate that Cu is essential for the monocyt differentiation process that contributes to the competency of host defense system.