Effect of retinoic acid on the proliferation and phagocytic capability of murine macrophage‐like cell lines

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Abstract
Retinoic acid (RA) exerted a variable degree of growth inhibitory activity on the macrophage‐like cell lines P388D1, J774.2, WEHI‐265, WEHI‐3, and PU‐5. Comparison of cell proliferation and clonal growth suggests that at concentrations of 10−9‐10−6 M the inhibitory activity stems from processes leading to elongation of cell cycle time and not from terminal differentiation processes. RA was shown to be a potent inducer of the development of high‐phagocytic phenotypes (assessed by phagocytosis of heat‐killed yeast cells) in the P388D1, J774.2, and WEHI‐265 cell lines which differ substantially in their proliferative and adherence characteristics. The PU‐5 and WEHI‐3 cell lines were not induced by RA to express an enhanced phagocytic activity toward heat‐killed yeast cells. The augmented phagocytic capability was dose dependent over a wide range of RA concentrations. In P388D1 cells, 2 × 10−12 M RA already exerted significant phagocytosis augmentation effects, which progressively increased up to 2 × 10−5 M RA, the highest concentration tested. Retinal, retinyl acetate, and retinol had similar effects to those of RA on both cell adherence and phagocytosis in P388D1 cells, albeit at concentrations four to six orders of magnitude higher. Optimal development of the high‐phagocytic phenotype in P388D1, J774.2, and WEHI‐265 cells required at least 96 hr of culture in the presence of RA; at 48 hr and 23 hr the effects were already substantial, whereas at 4 hr of exposure to RA no significant enhancement of phagocytosis could be detected. Thus both extended periods of culture in the presence of RA (more than two to three cell cycles) and high concentrations were needed for induction, in more than 90% of the cells, of the expression of a high‐phagocytic phenotype. The reversion to a low‐phagocytic phenotype upon removal of RA was also rather slow and required several cell cycles. In P388D1 cells RA also enhanced the phagocytosis of latex beads but had no effect on the phagocytosis of starch particles, or the extent of binding of immunoglobulin G‐coated sheep red blood cells (SRBC). The expression of receptors for concanavalin A and for nonopsonized SRBC remarkably increased in RA‐treated cells, as was the ability to perform Fc‐receptor mediated erythrophagocytosis. Both P388D1 cells and WEHI‐265 cells were induced by RA to express nitroblue tetrazolium reducing activity. The data suggest that RA induces profound changes in the functional capabilities of macrophage‐like cell lines which are apparently not dependent on cessation of growth and terminal differentiation processes.

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