Hepatocyte Growth Factor Is a Regulator of Monocyte-Macrophage Function

Abstract

Hepatocyte growth factor (HGF) is a potent paracrine mediator of stromal/epithelial interactions, which is secreted as a matrix-associated inactive precursor (pro-HGF) and locally activated by tightly controlled urokinase cleavage. It induces proliferation and motility in epithelial and endothelial cells, and plays a role in physiological and pathological processes involving invasive cell growth, such as angiogenesis and parenchymal regeneration. We now report that HGF induces directional migration and cytokine secretion in human monocytes. Monocyte activation by endotoxin and IL-1β results in the up-regulation of the HGF receptor expression and in the induction of cell-associated pro-HGF convertase activity, thus enhancing cell responsiveness to the factor. Furthermore, we provide evidence for the secretion of biologically active HGF by activated monocytes, implying an autocrine stimulation. Altogether, these data indicate that monocyte function is modulated by HGF in a paracrine/autocrine manner, and provide a new link between stromal environment and mononuclear phagocytes.

Silencing the MET oncogene leads to regression of experimental tumors and metastases

“…In fact, conventional inhibitors of MET-such as small tyrosine kinase inhibitors, antibodies or decoy molecules (Christensen et al, 2003;Kong-Beltran et al, 2004;Michieli et al, 2004;Petrelli et al, 2006;Smolen et al, 2006)-impair the activity of the receptor not only in tumors but also in host cells. This is critical, since MET functions have been linked also to neo-angiogenesis and host defense responses, as this oncogene is expressed in endothelial cells as well as in macrophages and in cells of the immune system (Bussolino et al, 1992;Galimi et al, 2001;Skibinski et al, 2001). Here, we show that MET silencing in cancer cells resulted in suppression of the invasive growth program in vitro, as demonstrated by cell inability to invade surrounding matrices, grow and form anchorage-independent colonies.…”

Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis

“…Although both DCs and macrophages have been described to be able to express c-met (Chen et al 1996;Galimi et al 2001;Ovali et al 2000;Rutella et al 2006) However, the presence of macrophages in the CNS at the onset phase of EAE, prior to the expression of c-met on splenic macrophages contradicts such a scenario.…”

“…However, the function of HGF/c-met signaling in monocytes/macrophages is at present a matter of debate with, functions ranging from migration to differentiation reported (Beilmann et al 1997;Beilmann et al 2000;Chen et al 1996;Galimi et al 2001;Jiang et al 2001). Although HGF/c-met signaling may directly influence leukocyte responses in inflammation and autoimmune diseases, the mechanisms involved remain at present poorly defined.…”

“…In general, HGF is thought to play a beneficial role in disease, stimulating repair mechanisms of damaged tissues. However, various types of leukocytes including macrophages (Chen et al 1996;Galimi et al 2001), monocytes (Beilmann et al 1997;Jiang et al 2001), dendritic cells (Ovali et al 2000;Rutella et al 2006), B cells (van der Voort et al 2000), and T cells (Adams et al 1994) have been described to either express c-met and/or show cellular responses to HGF indicating possible direct effects of HGF on leukocytes in inflammation.…”

Differential Role of Neutrophils and Alveolar Macrophages in Hepatocyte Growth Factor Production in Pulmonary Fibrosis

“…Sakai and colleagues found that human alveolar macrophages contained immunoreactive HGF, but they did not study HGF secretion by alveolar macrophages. LPS-stimulated human blood monocytes have been shown to secrete small amounts of HGF in vitro, whereas unstimulated monocytes do not (Galimi et al, 2001).…”