Inorganic arsenite alters macrophage generation from human peripheral blood monocytes
Introduction
Inorganic arsenic is a common constituent of the earth's crust and is widely distributed in soil and water (Morton and Dunnette, 1994, NRC, 1999). Humans encounter inorganic arsenic in drinking water from wells drilled into arsenic-rich strata (Morton and Dunnette, 1994, NRC, 1999). Endemic areas of overt arsenic poisoning have occurred in several countries in Asia and the Americas generally through the consumption of contaminated well water (Chen et al., 1986, Garcia-Vargas et al., 1991). In clinical investigations, it has been demonstrated that inorganic arsenic often induce abnormal inflammatory-like immunotoxicity in humans (Hall, 2002). The various severe inflammatory clinical observations, such as hypertrophy of the liver and/or spleen, were found at a higher rate of over 70% in chronic arsenic poisoning patients who ingested inorganic arsenic from contaminated well water in western Bengal, India (Guha-Mazumder, 1995). The medical observations of about 2000 chronic arsenic poisoning patients in Inner Mongolia, China, demonstrated that many cases of hepatomegaly, hardening of the liver, and splenomegaly were found (Asia Arsenic Network, 1997). It was also recently reported that long-term inorganic arsenic exposure was associated with an increased risk of cardiovascular diseases that were mediated by inorganic arsenic-induced vascular inflammation and subsequent carotid atherosclerosis in chronic arsenic poisoning patients in northeastern Taiwan, Republic of China (Wu et al., 2003). Thus, we concluded that investigations of the effects of inorganic arsenic on immune effector cells would be of great value in enhancing our understanding of the mechanism of its toxic effects in humans because there is little information on its effect on the immune system. Meng (1994) reported that low concentrations, nM–μM levels, of trivalent and pentavalent inorganic arsenicals, arsenite, and arsenate, significantly enhanced the DNA synthesis in phytohemagglutinin-stimulated human peripheral blood lymphocytes in vitro; however, other effects of the arsenicals on the human immune effector cells has not been well studied.
Human peripheral blood monocytes are among the important immature immune effector cells that are precursors of mature cells of macrophage lineage in the immune system. Monocytes can differentiate into macrophages by the macrophage colony stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF) (Akagawa, 2002, Akagawa et al., 1996, Komuro et al., 2001). Recently, we found that trivalent inorganic arsenite sensitively induced abnormal morphological changes in monocytes that were differentiating into macrophages by GM-CSF in vitro at nM concentrations, although other metallic compounds could not induce the same morphological changes (Sakurai et al., in press). In this study, we examined the details of the biological and/or toxicological effects of low concentrations, nM levels, of inorganic arsenicals, arsenite, or arsenate, on the CSF-induced differentiation of human monocytes into macrophages in vitro, because the total peripheral blood arsenic concentrations of chronic arsenic poisoning patients, who had inflammatory-like immune responses, were less than 1 μM (Pi et al., 2000, Wu et al., 2003).
Section snippets
Reagents
Sodium arsenite and sodium arsenate were purchased from Wako Pure Chemicals Co. (Osaka, Japan) and recrystallized twice. Their purity was >99.9% as determined by gas chromatography-mass spectrometry. Lipopolysaccharide (LPS) contamination of these arsenicals was not detected (<0.000 001%, wt/wt) using the LPS-specific limulus test (Seikagaku Co., Tokyo, Japan). 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) was purchased from the Sigma Chemical Co. (St. Louis, MO); dimethyl sulfoxide (DMSO) and
Arsenite altered the CSF-induced macrophage generation from human peripheral blood monocytes
Human peripheral blood monocytes were incubated in vitro with 1000 U/ml M-CSF or 5000 U/ml GM-CSF in the presence or absence of 5–500 nM inorganic arsenite or arsenate for 7 days, and the effect of arsenicals on the macrophage generation from the monocytes were observed. Monocytes incubated with M-CSF alone for 7 days differentiated into adhesive M-type macrophages (M-Mp) that were elongated and had a spindle-like morphology (Fig. 1). As shown in Fig. 2A, the addition of trivalent inorganic
Discussion
Humans take inorganic arsenicals through the consumption of contaminated well water, and these inorganic arsenicals are rapidly reduced and converted to a trivalent inorganic arsenite in human body. In this study, we demonstrated that arsenite had a modifying effect during the maturation of normal immune effector cells at nM levels, although a pentavalent inorganic arsenate had no effect on it; arsenite induced abnormal nonadhesive macrophage, As-Mp, generation from human peripheral blood
Acknowledgments
We express our thanks to Dr. Michael P. Waalkes (National Cancer Institute at National Institute of Environmental Health Science, National Institute of Health, Research Triangle Park, NC) and Dr. Yoshito Kumagai (University of Tsukuba, Ibaraki, Japan) for their valuable scientific advice on this paper, to Dr. Kiyoko S. Akagawa (National Institute of Infectious Diseases, Tokyo, Japan) for her technical advice for the monocyte preparation, to Dr. Masumi H. Sakurai (Azabu University, Kanagawa,
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Both authors contributed equally to this work.