A role for histamine in cytokine modulation by the adenosine A(3) receptor agonist, 2-Cl-IB-MECA.

The effects of adenosine receptor agonists on cytokine production in vivo were investigated in mouse models of endotoxemia. Selective adenosine A(3) (2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide) (2-Cl-IB-MECA) and A(2A) (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride) (CGS 21860) receptor agonists were found to modulate endotoxin-induced cytokine responses in mice sensitized to D-galactosamine or primed with Corynebacterium parvum. The adenosine receptor agonists had similar effects in these models of endotoxemia, suppressing the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 while enhancing that of interleukin-10.

The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models.

In this report, we describe experiments in which cannabinoid receptor ligands were evaluated for effects on the development of a peritoneal inflammation when elicited in mice with thioglycollate broth or staphylococcus enterotoxin A. The cannabinoid receptor agonists [(-)-11-hydoxy-Delta(8) tetrahydrocannabinol-dimethylheptyl] (HU-210) and [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methanone] (WIN 55212-2) blocked the migration of neutrophils into the peritoneal cavity in response to these inflammatory stimuli. This effect was caused by a delay in the production of the neutrophil chemoattractants, KC and macrophage inflammatory protein-2.

Modulation of cytokine responses in Corynebacterium parvum-primed endotoxemic mice by centrally administered cannabinoid ligands.

The cannabinoid receptor agonists [(-)-11-hydoxy-Delta(8)tetrahydrocannabinol-dimethylheptyl] (HU-210) and [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methanone] (WIN 55212-2) were previously shown to downregulate inflammatory cytokines (tumor necrosis factor alpha and interleukin-12) and to upregulate antiinflammatory interleukin-10 when administered intraperitoneally (i.p.) to mice before an endotoxin challenge.

Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice.

Previous studies have shown that mice primed with Corynebacterium parvum produce higher levels of inflammatory cytokines than unprimed mice upon challenge with lipopolysaccharide (LPS). Herein, we describe experiments in which two cannabinoid (CB) agonists, WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone) and HU-210 [(-)-11-hydroxy-delta(8) tetrahydrocannabinol-dimethylheptyl], were examined for their effects on LPS-induced cytokines in C. parvum-primed and unprimed mice.

Endogenous mouse interleukin-10 is up-regulated by exogenously administered recombinant human interleukin-10, but does not contribute to the efficacy of the human protein in mouse models of endotoxemia.

In murine models of experimental endotoxemia, inflammatory cytokines as well as antiinflammatory interleukin-10 (IL-10) appear in the circulation after the injection of lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced IL-10 is to down-regulate inflammatory cytokine production. Indeed, the protective effects of exogenously administered IL-10 against murine endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma).