CYTOCHALASIN-D INHIBITS LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR PRODUCTION IN MACROPHAGES

We reported previously that a reorganization of microfilaments can be observed when macrophages arc stimulated with lipopolysaccharide (LPS). This reorganization is not detected with current methods in macrophages of an LPS-nonresponsive C3H/HeJ mouse. These results suggest that the observed microfilament response might be involved in a macrophage-activating process induced by LPS. To investigate this, we studied the effect of cytochalasin D (CD), which inhibits reorganization of microfilaments, on LPS-induced tumor necrosis factor (TNF) production. A concentration of CD incapable of affecting filamentOus actin by itself was used in these experiments. When this concentration of CD was added after LPS stimulation, microfilament reorganization and TNF production were inhibited. The suppressive effect of CD on TNF production was confirmed by the observation that TNF-alpha mRNA expression was also inhibited by CD. This inhibitory effect of CD was not specific to TNF, because the production of interleukin-1 and prostaglandin E2 were also inhibited. These effects of CD were observed only when CD was added within the first 20 min after LPS stimulation. These results suggest that the CD-sensitive microfilament response is essential in the signaling pathway for the production of certain monokines in LPS-stimulated macrophages.