Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-alpha, MIP-1alpha, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin.
During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-kappaB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1alpha (MIP-1alpha), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-alpha, IL-12, MIP-1alpha, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1alpha, IL-6, and IFN-gamma. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-kappaB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes.
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest.
Z H
ZH
Németh
G
G
Haskó
E S
ES
Vizi
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019446:Endotoxemia / Q000188:drug therapy* / Q000401:mortality; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology*; D015996:Survival Rate; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
D000975:Antioxidants; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D009566:Nitrates; D009573:Nitrites; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; C020972:pyrrolidine dithiocarbamic acid; D009569:Nitric Oxide; D007371:Interferon-gamma