Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo

Raquel Tarazona, Ana González-García, Naoufal Zamzami, Philippe Marchetti, Nancy Frechin, José Angel Gonzalo, Mariano Ruiz-Gayo, Nico Van Rooijen, Carlos Martínez-A., Guido Kroemer

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

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-γ, 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.

Original languageEnglish
Pages (from-to)861-870
Number of pages10
JournalJournal of Immunology
Volume154
Issue number2
Publication statusPublished - 15 Jan 1995
Externally publishedYes

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