The impact of c-met/scatter factor receptor on dendritic cell migration

Abstract

Dendritic cells (DC) are professional antigen‐presenting cells that possess both migratory properties and potent T cell stimulatory activity, and that allow the uptake of antigenic material inperipheral tissues and its subsequent presentation in the T cell areas of lymphoid organs. Thus motility represents a central property that is required for DC function. Here we report on the expression of the receptor tyrosine kinase c‐met in DC. c‐Met is the high affinity receptor for scatter factor (SF)/hepatocyte growth factor, and ligand‐activated c‐met exhibits mitogenic, morphogenic andmotogenic activity in vivo and in vitro. c‐Met is signaling competent in DC since it is effectively tyrosine phosphorylated in response to SF ligand. It is demonstrated here that ligand‐activated c‐met regulates DC adhesion to the extracellular matrix component laminin but leaves antigen presenting function unaffected. Importantly, in ear sheet explant experiments activationof c‐met by ligand induces emigration of cutaneous DC (Langerhans cell, LC) from skin, but SF is not a chemoattractant factor for DC. Our results suggest an important role of the c‐met/SF system in DC/LC migration.

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…8 In contrast, apoptosis-or recombinant HGF-induced attraction of monocytes or iDC was not detected despite low level expression of the HGF receptor METon monocytes and iDC. Although HGF has been shown to enhance monocyte and iDC migration, it appears to increase motility rather than to act as a chemoattractant for these cells, 49,50 further confirming that the under-agarose migration assay used here is suitable to detect site-directed migration and not only changes in overall cellular motility.…”

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

“…However, whether its global immunomodulatory effect is pro-or antiinflammatory is still unclear. On the one hand, HGF is known to increase adhesion and migration of inflammatory cells of both the adaptive and the innate immune system (27)(28)(29). On the other hand, several antiinflammatory effects of HGF have been described, including (i) a Th2/T-helper cell type 3 (Th3) bystander deviation with increase of TGF-β and IL-10 (33, 40), (ii) inhibition of antigen-presenting cell (APC) function (40,41), (iii) down-regulation of monocyte chemotactic protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES) chemokines (42), and (iv) blocking of NF-κB function (42).…”

“…In addition to its action on the CNS, HGF shows immunomodulatory effects: on the one hand, HGF originally was reported to promote adhesion of B cells (27) and migration of T cells (28) as well as recruitment of dendritic cells (DC) (29). Moreover, HGF was reported to inhibit secretion of TGF-β (30), a potent antiinflammatory cytokine known to inhibit the progression of experimental autoimmune encephalomyelitis (EAE) (31).…”

A Novel Role for Bruton's Tyrosine Kinase in Hepatocyte Growth Factor-mediated Immunoregulation of Dendritic Cells

“…In addition to DCs; B cells, monocytes, T cells, and neutrophils either express c-MET and/or exhibit cellular responses to HGF (15)(16)(17)(18)(19). c-MET is a 190 kDa heterodimer composed of a 45 kDa extracellular ␣-chain and a disulfide-linked 145 kDa ␤-chain (20).…”