Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice

Abstract

Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.

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

“…HGF has been shown previously to be protective in various animal models of immune-mediated diseases such as myocarditis (32,33), glomerulonephritis (30,34), inflammatory bowel disease (35), collagen-induced arthritis (36), pulmonary fibrosis (37), allogeneic heart transplantation (45), graft-vs.-host disease (46), and asthma (47). According to these studies, HGF may ameliorate both Th1-type-dominated (33,36) and Th2-type-dominated (40,47) autoimmune responses.…”

“…According to these studies, HGF may ameliorate both Th1-type-dominated (33,36) and Th2-type-dominated (40,47) autoimmune responses. Interestingly, a recent report demonstrated that, in an experimental model of airway allergy, HGF might repress DC function without up-regulation of IL-10 (40).…”

“…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). On the other hand, HGF was identified more recently as having protective effects in animal models of inflammatory-mediated diseases including myocarditis (32,33), glomerulonephritis (30,34), inflammatory bowel disease (35), collagen-induced arthritis (36), and pulmonary fibrosis (37).…”

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

“…HGF has been reported to ameliorate the progression of a number of inflammatory autoimmune diseases, including allergic airway inflammation (7), myocarditis (8), lupus nephritis (9), and arthritis (10), suggesting that HGF may interfere with a common proinflammatory process. The protective actions of HGF in all of these various organ system dysfunctions were tightly associated with the modulation of T cell immune responses, supporting a potent regulation of DC function.…”

“…Within the hematopoietic compartment, c-Met is found constitutively expressed on progenitor cells and their Agpresenting progeny, including DCs, but is absent from T cells (6). Originally identified as a mitogen for hepatocytes, HGF acts as a potent regulator in multiple animal models of immunemediated disorders (7)(8)(9)(10), which suggests that HGF regulates key inflammatory events that are common to many diseases and organ systems. In particular, HGF has been demonstrated to re-strain the Ag-presenting function of mouse DCs (7) and to govern the development of Treg cell-inducing regulatory DCs (11,12).…”