Atherosclerosis 147 (1999) 33 – 40 Macrophage colony-stimulating factor reduces tert-butyl hydroperoxide induced oxidative injury to monocytes/macrophages Zhan-Jun Pang a, *, Mei Zhou a , Yuan Chen a , Jennifer Wan b a Laboratory of Free Radical Medicine, The First Military Medical Uniersity, Guangzhou 510515, People’s Republic of China b Zoology Department, Hong Kong Uniersity, Pokfulam Rd., Hong Kong Received 3 August 1998; received in revised form 17 February 1999; accepted 23 March 1999 Abstract The transformation of macrophages into foam cells is an important event in the development of atherosclerosis, and the oxidative injury caused by oxidized low density lipoprotein (Ox-LDL) plays an essential role in that process. It has been proved that macrophage colony-stimulating factor (M-CSF) could prevent the progression of atherosclerosis in Watanabe heritable hypercholesterolemic (WHHL) rabbits. We proposed that the anti-atherogenic effect of M-CSF was partly associated with its protective effect on monocyte-derived macrophages from Ox-LDL induced oxidative injury. In order to prove this, we investigated the effect of M-CSF on the oxidative injury caused by tert-butyl hydroperoxide (tbOOH) to mouse peritoneal macrophages and U937/J774 cell lines. The results showed that M-CSF could protect mouse peritoneal macrophages from oxidative injury (presented by cell morphology and cell survival rate); L929 cell-conditioned medium (L929-CM) had the same effect as M-CSF; and anti-M-CSF monoclonal antibody could mostly block the protective effect of L929-CM on macrophages. L929-CM was proved to be also able to decrease the impact of plasma membrane fluidity in U937 and J774 cells treated with tbOOH. Incubation with tbOOH caused DNA fragmentation in U937 cells. The presence of L929-CM greatly reduced the number of apoptotic U937 cells characterized by DNA fragmentation. From these results, we concluded that M-CSF could protect monocytes/macrophages from oxidative injury. It may be one of the mechanisms which explain the anti-atherogenic effect of exogenous M-CSF in WHHL rabbits. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Macrophage colony-stimulating factor; Macrophage; Oxidative stress; U937 cell line; J774 cell line www.elsevier.com/locate/atherosclerosis 1. Introduction Infiltration of monocytes into arteries is an early event in atherogenesis [1]. And monocyte-derived foam cell formation is intensively associated with the progres- sion of atherosclerosis. Lines of evidence have shown that oxidized low density lipoprotein (Ox-LDL) and macrophage colony-stimulating factor (M-CSF) are two of the factors that play important roles in these procedures. Ox-LDL can induce the infiltration of cir- culating monocytes into artery wall [2]. M-CSF can induce the expression of scavenger receptor, the matu- ration and differentiation of monocytes, and increase the uptake of Ox-LDL by monocyte-derived macrophages [3]. Ox-LDL can also cause lipoperoxida- tive injury and transform monocytes/macrophages into foam cells [4]. In this hypothesis, M-CSF seems to promote the development of atherosclerosis in the early stage. But M-CSF cannot be simply seen to promote the progression of atherosclerosis. Although the recruit- ment of monocytes is usually interpreted as enhancing lesion development, it could also be a host response limiting lipid accumulation. The ability of monocyte- derived macrophages to limit cholesterol uptake, how- ever, can be reduced by the impaired mobility and metabolic activity associated with foam cell develop- ment. As lesions enlarge, foam cells die and become the nidus for the necrotic core. Treatments to improve viability might improve foam cell function and promote regression. Macrophage colony-stimulating factor (M- CSF) is vital to monocyte/macrophage differentiation, proliferation, and activation [5]. However, foam cells of Watanabe heritable hyperlipidaemic (WHHL) rabbits * Corresponding author. 0021-9150/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(99)00159-8