HUMAN MONOCYTES EXPRESS AMPHIREGULIN AND HEREGULIN GROWTH-FACTORS UPON ACTIVATION

In the last few years, three new heparin binding growth factors that i nteract with the Epidermal Growth Factor receptor (EGFR) and/or the re lated p185(erbB-2) tyrosine kinase have been identified. Amphiregulin (AR) and Heparin-Binding EGF-like growth factor (HB-EGF) bind and acti vate the EGFR while Heregulin (HRG) acts through the p185(erbB-2) and p180(erbB-4) tyrosine kinases. Recently, activated macrophages were re ported to secrete a p185(erbB-2) - and a heparin binding EGFR- stimula tory activities. We show here that activated monocytes secrete AR, HRG and HB-EGF-like molecules. Indeed, upon activation with Phorbol12, 13 -dibutyrate (PDBu), the human monocytic-like THP-1 cells expressed hig h levels of AR, HRG and HB-EGF transcripts and released heparin bindin g factors that induced tyrosine phosphorylation of the EGFR in A431 ce lls and a protein of 185 kDa in MDA MB 453 cells. Similarly, activatio n of peripheral blood monocytes induces a dramatic increase of these t hree genes. Since EGFR, c-erbB-2, c-erbB-4 transcripts are not or hard ly detected upon activation, the occurrence of autocrine loops in thes e cells is unlikely. Therefore, secretion of these factors by activate d monocytes may be implicated in the paracrine activation of the erb r eceptors thereby contributing to the epithelial and connective tissue proliferation.