AUTOCRINE SIGNALS CONTROL CCAAT ENHANCER-BINDING PROTEIN-BETA EXPRESSION, LOCALIZATION, AND ACTIVITY IN MACROPHAGES

The transcription factor CCAAT/enhancer binding protein beta (C/EBP be ta, or NF-IL6) is expressed in macrophages, where it participates in l ipopolysaccharide (LPS)-mediated induction of proinflammatory cytokine genes such as interleukin-6 (IL-6) and IL-1 beta. We have identified activities in conditioned medium from a macrophage tumor cell line tha t regulates the expression, localization, and transcriptional activity of C/EBP beta. One factor was shown to be tumor necrosis factor-alpha (TNF-alpha), which increased C/EBP beta expression by a posttranscrip tional mechanism. A second activity, designated autocrine macrophage f actor (AMF), elicited a change in C/EBP beta localization from a punct ate nuclear staining pattern to diffuse nuclear distribution. The punc tate form of C/EBP beta correlated with increased susceptibility of th is protein to cleavage by an endogenous protease during nuclear extrac t preparation. Conditioned medium stimulated the ability of C/EBP beta to transactivate a reporter gene and activated the expression of two cytokine genes that are putative targets of C/EBP beta. These observat ions suggest that diffuse distribution of C/EBP beta in the nucleus co rresponds to an activated form of this protein. AMF activity could not be mimicked by an extensive set of recombinant cytokines and growth f actors and therefore may represent a novel extracellular factor. This is a US government work. There are no restrictions on its use.