In vitro inhibition of enterobacteria-reactive CD4+CD25- T cells and suppression of immunoinflammatory colitis in mice by the novel immunomodulatory agent VGX-1027.
VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role of innate immunity in inflammatory bowel diseases prompted us to consider the use of VGX-1027 in these diseases leading us to in vitro and in vivo test the drug in related experimental conditions. These consist, respectively, of the proliferation assay of CD4+CD25- T cells to enterobacteria, and the acute inflammatory colitis induced in mice by intracolonic challenge with dinitrobenzene sulfonic acid. The data from the two sets of experiments revealed that VGX-1027 inhibited both proliferation of enterobacterial antigen-reactive CD4+CD25- T cells in vitro and the development of clinical and histological signs of colitis in vivo. The beneficial effect in this model was associated with reduced colonic production of proinflammatory cytokines such as interleukin (IL)-1beta, TNF-alpha, IL-12p70 and interferon (IFN)-gamma and lower content of nuclear factor (NF)-kappaB (p65). These findings seem to warrant investigations of VGX-1027 for use in human.
Mangano
Katia
K
Department of Biomedical Sciences, Section of Clinical Pathology and Molecular Oncology, University of Catania, Italy.
Sardesai
Niranjan
N
D'Alcamo
Maria
M
Libra
Massimo
M
Malaguarnera
Lucia
L
Donia
Marco
M
Bendtzen
Klaus
K
Meroni
Pierluigi
P
Nicoletti
Ferdinando
F
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D049109:Cell Proliferation; D002469:Cell Separation; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003967:Diarrhea / Q000188:drug therapy; D004755:Enterobacteriaceae / Q000187:drug effects*; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000188:drug therapy; D007155:Immunologic Factors / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D051996:Transcription Factor RelA / Q000187:drug effects
C518641:3-phenyl-4,5-dihydro-5-isoxazole acetic acid; D000085:Acetates; D016207:Cytokines; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010080:Oxazoles; D051996:Transcription Factor RelA; D009195:Peroxidase