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J Biol Chem. 1998 May 8;273(19):11583-8.

Autocrine regulation of macrophage differentiation and 92-kDa gelatinase production by tumor necrosis factor-alpha via alpha5 beta1 integrin in HL-60 cells.

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  • 1Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, Argonne, Illinois 60439-4833, USA.


Tumor necrosis factor-alpha (TNF-alpha) gene is one of the early response genes induced by phorbol 12-myristate 13-acetate (PMA) in human HL-60 myeloid leukemia cells. In the present study, we examined the role of the TNF-alpha autocrine loop in PMA-induced macrophage differentiation and gene expression of 92- and 72-kDa gelatinases (MMP-9 and MMP-2). In HL-60 cells, PMA inhibited cell proliferation and induced cell adhesion and spreading, expression of surface maturation marker OKM1 and phagocytic activity, as well as the expression of both gelatinases, which all characterize the macrophage phenotype. In contrast, TNF-alpha alone was only effective in inhibiting cell proliferation. Blocking the endogenous TNF-alpha activity with neutralizing anti-TNF-alpha antibodies abolished all these PMA-induced events with the exception of MMP-2 gene expression. Since fibronectin (FN)-mediated cell adhesion and spreading are prerequisite for both macrophage differentiation and MMP-9 gene expression in HL-60 cells, we hypothesized that TNF-alpha might be involved in modulating the expression of either the FN or its integrin receptor genes. Whereas PMA substantially enhanced the steady state mRNA and protein levels of both FN and alpha5 beta1 integrins, TNF-alpha alone had little effect on the expression of these genes. However, anti-TNF-alpha antibodies blocked PMA-induced augmentation of both alpha5 and beta1 integrin gene expression without affecting the expression of the FN gene. Our results suggest that TNF-alpha may regulate macrophage differentiation and critical matrix-degrading activities of myeloid progenitor cells in an autocrine manner by augmenting surface levels of the alpha5 beta1 integrin, thus promoting interactions with the extracellular matrix, a key event for maturation and migration of these cells during inflammation.

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