EFFECT OF LIPOPOLYSACCHARIDE ON THYMIDINE SALVAGE AS RELATED TO MACROPHAGE ACTIVATION

Lipopolysaccharide (LPS), known as one of the potent activators of mac rophages, has inhibitory effects on the proliferation of normal macrop hages and macrophage-like cell lines. We report here that LPS dose- an d time-dependently suppressed the tritiated thymidine ([H-3]TdR) incor poration into the acid-insoluble fraction with a significant inverse c orrelation to the tumour necrosis factor-alpha (TNF) production in the J774.1 macrophage cell line. Among the three tested enzymes involved in DNA synthesis, only thymidine kinase (TK) activity decreased progre ssively in parallel with the decline in [H-3]TdR incorporation, reachi ng 97% inhibition within 12 hr of LPS treatment, while changes in the activities of other two enzymes, DNA polymerase oc and thymidylate syn thase (TS), were less significant. On the other hand, LPS inhibited th e cell proliferation only incompletely, as judged by 62% inhibition of cell growth at 36 hr. Even in the experiments done in a TdR-free medi um, cell growth was inhibited by LPS to the same extent, suggesting th at TK was not directly involved in the proliferation of J774 cells. LP S also inhibited the conversion of TdR to thymidine monophosphate (TMP ) in murine peritoneal exudate macrophages (PEM). Thus LPS-induced sup pression of TdR salvage related to TNF production is common in both no rmal and neoplastic macrophages, and therefore may be of potential imp ortance in the process of macrophage activation.