Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo.
Chlorpromazine (CPZ) has potent immunomodulatory effects in vivo; it induces humoral autoimmunity in up to 50% of patients, inhibits delayed-type hypersensitivity reactions, and suppresses lethal immune hyperactivation in animal models of septic shock. Here, we show that in an in vivo model of acute superantigen-driven immune activation, CPZ independently down-regulates the production of various T cell-derived lymphokines (IL-2, IFN-gamma, IL-4, TNF, and GM-CSF) and up-regulates the secretion of IL-10. Whereas only low, if any, serum IL-10 levels are detectable by ELISA after injection of CPZ, bacterial LPS, or staphylococcal enterotoxin B (SEB) alone, simultaneous administration of CPZ + LPS or CPZ + SEB causes a significant increase in IL-10 production in vivo. CPZ-mediated amplification of the SEB-driven CPZ secretion is accompanied by an enhanced IL-10 mRNA accumulation, as shown by PCR analysis and in situ hybridization. Determination of IL-10 production in mice lacking T cells, B cells, or phagocytes revealed that SEB + CPZ-induced IL-10 was produced by phagocytic cells, but not by lymphocytes, a finding that is in accord with the distribution of splenic cells transcribing the IL-10 gene in response to SEB + CPZ. Moreover, these data indicate that bacterial superantigen can directly stimulate tissue phagocytes, even in the virtual absence of T lymphocytes. The blockade of dopamine type 1 (D1) but not type 2 (D2) receptors abolishes the CPZ effect on IL-10 production. Inhibition of Th1 and Th2 lymphokine production by CPZ is not mediated by dopamine receptors and is independent of IL-10 up-regulation. These findings may explain the mechanism by which CPZ and related drugs enhance humoral autoimmune reactions, block cellular immune responses, and prevent lethal septic shock in vivo.
Tarazona
R
R
National Center for Biotechnology, Autonomous University of Madrid, Spain.
González-García
A
A
Zamzami
N
N
Marchetti
P
P
Frechin
N
N
Gonzalo
J A
JA
Ruiz-Gayo
M
M
van Rooijen
N
N
Martínez
C
C
Kroemer
G
G
D000818:Animals; D001483:Base Sequence; D002746:Chlorpromazine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000276:immunology; D017403:In Situ Hybridization; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012772:Shock, Septic / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects
D016207:Cytokines; D004768:Enterotoxins; D008070:Lipopolysaccharides; D018089:Superantigens; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D002746:Chlorpromazine