Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features.
Several hematopoietic growth factors, including interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1), promote the differentiation of tolerogenic dendritic cells (DCs). Hepatocyte growth factor (HGF) is a pleiotropic cytokine whose effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGFMo) differentiated into accessory cells with DC-like morphology, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. Upon activation with HGFMo, allogeneic CD4+CD25- T cells expressed the T regulatory (Treg)-associated transcription factor FoxP3, proliferated poorly, and released high levels of IL-10. Interestingly, blockade of surface immunoglobulin-like transcript 3 (ILT3) on HGFMo or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Secondary stimulation of HGFMo-primed CD4+ T cells with immunogenic DCs differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 from monocytes of the same donor resulted in measurable T-cell proliferation. HGFMo-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25- T cells in a cell-contact-dependent manner. Finally, DNA microarray analysis revealed a unique gene-expression profile of HGF-activated monocytes. Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions that might be exploited therapeutically.
Rutella
Sergio
S
Department of Hematology, Laboratory of Immunology, Catholic University Medical School, Largo A. Gemelli 8-00168 Rome, Italy. srutella@rm.unicatt.it
Bonanno
Giuseppina
G
Procoli
Annabella
A
Mariotti
Andrea
A
de Ritis
Daniela G
DG
Curti
Antonio
A
Danese
Silvio
S
Pessina
Gloria
G
Pandolfi
Simona
S
Natoni
Federica
F
Di Febo
Annalaura
A
Scambia
Giovanni
G
Manfredini
Rossella
R
Salati
Simona
S
Ferrari
Sergio
S
Pierelli
Luca
L
Leone
Giuseppe
G
Lemoli
Roberto M
RM
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D010641:Phenotype; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D016753:Interleukin-10; D018664:Interleukin-12; D017228:Hepatocyte Growth Factor