Dopamine suppresses IL-12 p40 production by lipopolysaccharide-stimulated macrophages via a β-adrenoceptor-mediated mechanism
Introduction
Multiple regulatory interactions have been demonstrated between the central nervous system, neuroendocrine axis, and immune system Besedovsky and del Rey, 1996, Haskó and Szabó, 1998, Straub et al., 1998, Xaus et al., 1999, Elenkov et al., 2000, Chunn et al., 2001. The immunomodulatory effects of the neurotransmitters acetylcholine, norepinephrine and adenosine are well documented, but so far the regulatory action of the dopaminergic system on the immune system has been less well investigated. Several cell types of the immune system including lymphocytes and natural killers cells express dopamine receptors Le Fur et al., 1980, Santambrogio et al., 1993, Ricci et al., 1994, however there is only indirect evidence demonstrating that cells of the monocyte/macrophage linage are equipped with dopamine receptors. For example, dopamine has been reported to suppress IFN-γ-induced Ia expression (Sternberg et al., 1986) and stimulate IFN-γ-induced phagocytosis (Sternberg et al., 1987) in murine bone marrow macrophages. However, both of these studies failed to demonstrate that the effects of dopamine were mediated by ligation of dopamine receptors.
IL-12 p40 is part of two heterodimeric cytokines that are secreted mainly by activated antigen-presenting cells and play a key role in determining the nature of the immune response to exogenous or endogenous antigens. IL-12 p70 is a composite of IL-12 p40 and IL-12 p35 (Trinchieri, 1995), while IL-12 p40 engages p19 to form IL-23 (Oppmann et al., 2000). Both IL-12 and IL-23 enhance the proliferation, cytotoxicity, and production of IFN-γ by T lymphocytes and natural killer cells Trinchieri, 1995, Oppmann et al., 2000, which is essential for the clearance of bacterial infections Trinchieri, 1995, Oppmann et al., 2000. Mice that are genetically deficient in IL-12 p40 are highly susceptible to infection with various intracellular pathogens (Mattner et al., 1996). On the other hand, IL-12 p40 is an important pathogenetic factor in autoimmune disease. This is demonstrated by the fact that IL-12 p40 deficient mice are resistant to collagen-induced arthritis (McIntyre et al., 1996), while transgenic overexpression of IL-12 p40 exacerbates the course of this disease (Parks et al., 1998).
Previous studies have shown that the catecholamines norepinephrine and epinephrine are potent suppressors of the production of IL-12 Elenkov et al., 1996, Panina-Bordignon et al., 1997, Haskó et al., 1998. In the present study, we tested whether dopamine regulated the production of IL-12 p40. Our results demonstrate that dopamine inhibits IL-12 production, which is mediated by both β-adrenoceptor-dependent and independent pathways.
Section snippets
Reagents and drugs
LPS (serotype 055:B5), dopamine, propranolol, the D1 receptor antagonist R-(+)-SCH-23390 HCl and D2 receptor antagonist raclopride were obtained from Research Biochemicals Inc. (Natick, MA). RPMI 1640, fetal bovine serum, and penicillin–streptomycin were obtained from Life Technologies™ (Grand Island, NY).
Preparation of peritoneal macrophages
The experiments described in this article were performed in adherence to National Institute of Health guidelines on the use of experimental animals. All experiments were performed in adherence
Dopamine suppresses IL-12 p40 production
To assess the effect of dopamine on IL-12 p40 production by macrophages, we pretreated J774 cells with increasing concentrations of dopamine (0.01–100 μM) that was followed by stimulation of the cells with LPS for 24 h. Fig. 1a demonstrates that dopamine suppressed IL-12 p40 production in a concentration-dependent manner. This effect of dopamine was not due to a non-specific inhibition of cell viability, because dopamine did not decrease cell respiration as measured using the MTT assay (Fig. 1b)
Discussion
Transmitters of the sympathetic nervous system are important regulators of IL-12 p40 production. Elenkov et al. (1996) were the first to report that both norepinephrine and epinephrine are potent inhibitors of IL-12 release in human whole blood (Elenkov et al., 1996). These stress hormones act through β2-adrenoceptors located on monocytes and dendritic cells and the mechanism of action involves a transcriptional inhibition of both the p35 and p40 subunits and posttranslational inhibition of p35
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