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Induction of Macrophage-Like Differentiation of HL-60 Leukemia Cells by Tumor Necrosis Factor-: Potential Role of fos Expression

Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center New Orleans, Louisiana 70119
Department of Pharmacology, Louisiana State University Medical Center New Orleans, Louisiana 70119
Department of Oral Pathology, Louisiana State University Medical Center New Orleans, Louisiana 70119

Address requests for reprints to: Stephen P. Squinto, Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, 1100 Florida Avenue, New Orleans, Louisiana 70199.

Abstract

Tumor necrosis factor- (TNF-) is a macrophage-derived cytokine elicited during cellular responses to various microbial infections. TNF- exerts direct cytotoxicity toward some tumor cells in vitro and produces hemorrhagic tumor necrosis in vivo. In human promyelocytic HL-60 leukemia cells, human recombinant TNF- (rTNF-) exhibits a small early proliferative effect (within 48 h), followed by marked cytostatic activity at 96 h after the addition of rTNF-. Cytostasis is contiguous with an induction of cell differentiation along the monocyte/macrophage lineage. The cell proliferation effects and the induction of the differentiated phenotype are preceded by an approximate 5-fold increase in c-fos mRNA levels within 90 min after rTNF- treatment of log phase HL-60 cells. Nuclear in vitro transcription assays indicate that the effect of rTNF- on c-fos mRNA abundance is controlled at the transcriptional level. We have also used a postembedding immunocolloidal gold electron microscopy technique to localize and semiquantitate pp55^c-fos proto-oncoprotein levels in the nucleus of both control and rTNF--treated HL-60 leukemia cells. In response to rTNF-, we have observed a rapid and transient accumulation of pp55^c-fos in discrete nuclear substructures within 2 h after treatment. C-fos staining appears in clusters, which are preferentially localized over semicondensed chromatin and interchromatin granules. These results suggest that pp55^c-fos is involved in the signal transduction system initiated by rTNF- during the induction of HL-60 differentiation.

FOOTNOTES

This work was supported by a grant from the Cancer Association of New Orleans (to S.P.S.) and a predoctoral fellowship from the same organization (to J.P.D.).

Received for publication September 1, 1988. Accepted for publication November 11, 1988.