ACQUISITION OF SECRETION OF TRANSFORMING GROWTH-FACTOR-BETA-1 LEADS TO AUTONOMOUS SUPPRESSION OF SCAVENGER RECEPTOR ACTIVITY IN A MONOCYTE-MACROPHAGE CELL-LINE, THP-1

Macrophage cells derived from the human monocytic leukemia cell line, THP-1, accumulate esterified cholesterol when cultivated in the presen ce of acetylated low density lipoprotein (Ac-LDL) through scavenger re ceptors (ScR). In the present study, we isolated a subtype of THP-1 ce lls that failed to accumulate esterified cholesterol when cultivated i n the presence of Ac-LDL. The cells had negligible amounts of cell ass ociation and degradation of Ac-LDL compared with the parent THP-1 cell s. The subtype THP-1 cells did not express ScR mRNA as well as that of lipoprotein lipase. In contrast, the expression of apolipoprotein E m RNA was greater than that found in parent THP-1 cells. The culture med ium of subtype THP-1 cells treated with 12-O-tetradecanoylphorbol-13-a cetate inhibited the uptake of Ac-LDL and the expression of ScR in par ent THP-1 cells. After a 48-h incubation in the culture medium contain ing 12-O-tetradecanoylphorbol-13-acetate, the culture medium of differ entiated subtype THP-1 cells contained 6.9 ng/ml transforming growth f actor (TGF)-beta 1, while that of parent THP-1 cells secreted below de tection level, which was less than 3 ng/ml. This inhibitory effect of the conditioned medium on the expression of ScR in parent THP-1 cells was abolished by pretreatment of the culture medium with anti-TGF-beta 1 antibodies. Parent THP-1 cells expressed as much TGF-beta 1 mRNA as sTHP-1 cells after stimulation of differentiation. Although the precu rsor forms of TGF-beta 1 that were synthesized in both parent and subt ype THP-1 cells were of similar size and were expressed at similar lev els, latent TGF-beta 1-binding protein, which is necessary for the sec retion of TGF-beta 1, could only be co-immunoprecipitated with antiTGF -beta 1 antibody from subtype THP-1 cells. This suggests that subtype THP-1 cells secrete TGF-beta 1 into the medium by forming a functional complex with the latent TGF-beta 1-binding protein. We conclude that subtype THP-1 cells could not take up Ac-LDL because ScR was inhibited (leading to a loss of function) caused by the secreted TGF-beta 1.