title: Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice.
abstract: We have previously shown that chlorpromazine (CPZ) inhibits tumour necrosis factor (TNF) production and protects against endotoxic shock in mice. In this paper we investigated the effect of pretreatment with CPZ, 4 mg/kg i.p. 30 min before, compared with dexamethasone (DEX; 3 mg/kg) on the induction of other endotoxin (lipopolysaccharide; LPS)-induced cytokines in the serum of mice, i.e. interleukin-1 alpha (IL-1 alpha), IL-6 and IL-10, and TNF. We also studied the effect of CPZ on serum and spleen-associated TNF. Both DEX and CPZ inhibited TNF production, whereas induction of IL-1 and IL-6 was inhibited by DEX but not by CPZ. DEX did not affect IL-10, while CPZ potentiated its induction. CPZ also inhibited spleen-associated TNF induction in LPS-treated mice, suggesting an effect on the synthesis of TNF. CPZ inhibited TNF induction by Gram-positive bacteria (heat-killed Staphylococcus epidermidis) and by anti-CD3 monoclonal antibodies. Intraperitoneal administration of CPZ also inhibited the induction of brain-associated TNF induced by intra-cerebroventricular injection of LPS. Therefore, CPZ is a more specific inhibitor of TNF production than DEX; in particular, CPZ increased the induction of IL-10, which is a 'protective' cytokine known to inhibit LPS toxicity and TNF production. CPZ inhibited TNF production in vivo, irrespective of the TNF stimulus used to induce TNF. Finally, CPZ did not induce the 'rebound' effect of DEX that, when given 24 hr before LPS, potentiates TNF production, but it did inhibit TNF production after 24 hr.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mengozzi
authors.forename: G
authors.initials: G
authors.lastname: Fantuzzi
authors.forename: R
authors.initials: R
authors.lastname: Faggioni
authors.forename: A
authors.initials: A
authors.lastname: Marchant
authors.forename: M
authors.initials: M
authors.lastname: Goldman
authors.forename: S
authors.initials: S
authors.lastname: Orencole
authors.forename: B D
authors.initials: BD
authors.lastname: Clark
authors.forename: M
authors.initials: M
authors.lastname: Sironi
authors.forename: F
authors.initials: F
authors.lastname: Benigni
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000276:immunology*; D002746:Chlorpromazine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013212:Staphylococcus epidermidis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000942:Antigens, Bacterial; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone; D002746:Chlorpromazine