In vitro, ex vivo and in vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in murine models

Ivana Stojanovic; Salvatore Cuzzocrea; Katia Mangano; Emanuela Mazzon; Djordje Miljkovic; Mingjun Wang; Marco Donia; Yousef Al Abed; Joseph Kim; Ferdinando Nicoletti; Stanislava Stosic-Grujicic; Mogens Claesson

doi:10.1016/j.clim.2007.03.004

In vitro, ex vivo and in vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in murine models

Clin Immunol. 2007 Jun;123(3):311-23. doi: 10.1016/j.clim.2007.03.004. Epub 2007 Apr 20.

Authors

Ivana Stojanovic¹, Salvatore Cuzzocrea, Katia Mangano, Emanuela Mazzon, Djordje Miljkovic, Mingjun Wang, Marco Donia, Yousef Al Abed, Joseph Kim, Ferdinando Nicoletti, Stanislava Stosic-Grujicic, Mogens Claesson

Affiliation

¹ Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia and Montenegro.

PMID: 17449326
DOI: 10.1016/j.clim.2007.03.004

Abstract

We have presently studied the in vitro, ex vivo and in vivo immunopharmacological effects of VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid]. This compound reduced the secretion of IL-1beta, TNF-alpha and IL-10 from purified murine macrophages stimulated "in vitro" with lipopolysaccharide (LPS), and it also modified the signaling pathways induced in these cells by LPS entailing reduced activation of NF-kappaB and p38 MAP kinase pathways along with up-regulation of ERK pathways. VGX-1027 appeared to spare T cell function as it was unable to modify the proliferation and/or secretion of IL-2, IFN-gamma and IL-4 induced in purified murine CD4+ T cells from stimulation with either CD3+CD28 or ConA. These effects on macrophages may account for the capacity of VGX-1027 to markedly ameliorate the course of both acute and chronic immunoinflammatory diseases in mice such as carrageenan-induced pleurisy, LPS-induced lethality and type II collagen-induced arthritis. Acute and subacute toxicological studies show that the drug is not toxic at the doses that exert biological effects in these preclinical models. These data warrant additional studies for the potential use of VGX-1027 in the clinical setting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetates / pharmacology*
Acetates / toxicity
Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
Animals
Arthritis, Experimental / chemically induced
Arthritis, Experimental / pathology
Arthritis, Experimental / prevention & control*
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Cytokines / metabolism*
Female
I-kappa B Proteins / metabolism
Immunologic Factors / pharmacology
Immunologic Factors / toxicity
Leukocytes, Mononuclear / drug effects*
Leukocytes, Mononuclear / metabolism
Lipopolysaccharides / pharmacology
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Inbred DBA
Mitogen-Activated Protein Kinases / metabolism
Oxazoles / pharmacology*
Oxazoles / toxicity
Phosphorylation / drug effects
Pleurisy / chemically induced
Pleurisy / pathology
Pleurisy / prevention & control*
Shock, Septic / chemically induced
Shock, Septic / mortality
Shock, Septic / prevention & control*
Spleen / cytology
Spleen / drug effects
Survival Rate

Substances

3-phenyl-4,5-dihydro-5-isoxazole acetic acid
Acetates
Cytokines
I-kappa B Proteins
Immunologic Factors
Lipopolysaccharides
Oxazoles
Acetylmuramyl-Alanyl-Isoglutamine
Mitogen-Activated Protein Kinases