Lipopolysaccharide and phorbol 12-myristate 13-acetate both impair monocyte differentiation, relating cellular function to virus susceptibility

Both lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) imp eded monocyte to macrophage differentiation with respect to typical phenoty pic modulation and certain phagocyte-related processes. The down-regulation of the porcine monocyte marker SWC1, and up-regulation of the SWC9 macroph age marker were retarded, but not inhibited, as was the differentiation-ass ociated down-regulation of p53 and myeloperoxidase. Despite this clear impa irment of macrophage differentiation, not all cellular functions were equal ly susceptible. Both agents inhibited phagocytosis, but not low-density lip oprotein receptor-associated endocytosis. Only LPS inhibited tartrate-resis tant acid phosphatase up-regulation. In contrast, increase of vacuolar acid ification rates was more susceptible to PMA. The activity of certain endoso mal/lysosomal enzymes - esterase, nucleotidase, peroxidase and cathepsins - was generally enhanced by both LPS and PMA. This contrasted with autophago somal activity, detected through the induction of an antiviral state. Disru ption of autophagosomes and lysosomes (methionine-O-methyl ester), but not lysosomes alone (glycyl-l-phenylalanine) reversed LPS-induced inhibition of virus replication, without influencing the PMA-induced antiviral effect. T hus, PMA is similar to LPS in inhibiting monocyte to macrophage differentia tion, when primary blood monocytes are employed, but not all pathways are e qually susceptible. The analyses demonstrate that the pathways modulated du ring monocyte differentiation function somewhat independently. Moreover, ce rtain functions of monocytic cells are more important with respect to the o utcome of virus infection, with autophagosomal activities in particular fav ouring cell survival.