Catecholamines trigger IL-10 release in acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells

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Abstract

Acute stress reactions (e.g. linked with trauma, major surgery, psychic stress and myocardial infarction) are accompanied with temporary systemic release of the anti-inflammatory cytokine IL-10 followed by immunodepression. Since an association between activation of the sympathetic system and IL-10 release has been described, we studied the influence of catecholamines on its promoter activity in vitro. Using reporter gene assays we demonstrated that catecholamines in monocytic cells directly stimulate the IL-10 promoter/enhancer via a cAMP/protein kinase A-dependent pathway. A cAMP responsive element was identified as major target. Thus, catecholamines are directly involved in the regulation of immunoresponsiveness under stressful conditions.

Introduction

The unspecific inflammatory system (macrophages, mast cells, complement system) responds quickly to invading pathogens and tissue destruction. In addition, ‘dangerous’ signals (e.g. naked DNA, heat shock proteins, debris from necrotic cells, incompletely glycosylated carbohydrates, vascular disruption) trigger antigen presenting cells that stimulate the specific immune response. However, unrelenting immune attack is not advantageous to the host. All beneficial immune response must stop, even if antigen persists. Therefore, both antigen specific and unspecific inflammatory immune response is well controlled. In addition to direct feedback loops within the immune system, the neuroendocrine system including the activation of the stress axis, plays an important control function. Whereas the hypothalamo-pituitary-adrenal (HPA) axis and the immunosuppressive action of corticosteroids are well investigated, the mechanism of catecholamine-related immune alterations have not yet been fully elucidated. It has been shown in vitro and in vivo, that epinephrine and norepinephrine may downregulate inflammatory response, particularly by targeting monocytes/macrophages and T lymphocytes and attenuating excessive synthesis of pro-inflammatory cytokines (TNF-α, IL-1β, IL-12), as well as elevating anti-inflammatory cytokines (IL-10, IL-1 receptor antagonist) via a β-adrenoreceptor-dependent and cAMP/protein kinase A (PKA) mediated pathway (Suberville et al., 1996, Van der Poll et al., 1996, Van der Poll and Lowry, 1997, Kavelaars et al., 1997, Hasko et al., 1998, Siegmund et al., 1998). The immunosuppressive cytokine IL-10 plays an important role in the regulation of the specific and unspecific inflammatory response. IL-10 deficient mice develop severe colitis and anemia as a result of uncontrolled inflammation (Kuhn et al., 1993). Recently, we have demonstrated that catecholamines also induce de novo IL-10 synthesis by monocytes in vitro and are responsible for the rapid systemic IL-10 release after sympathetic activation in vivo, thus contributing to immunodepression after brain injury and neurosurgery in the absence of systemic inflammation (Woiciechowsky et al., 1998). Systemic IL-10 upregulation is not limited to brain injury but is also detectable after major surgery and trauma (Döcke et al., 1997a). Following myocardial infarctions — a very stressful event with strongly elevated systemic catecholamine levels (2.5–3-fold higher than controls) — patients showed increased IL-10 plasma levels (up to 55 pg/ml) during the first 2 days after the event which were associated with a temporary attenuation of monocytes with regards to their antigen presenting activity and TNF releasing capacity (Shibata et al., 1997, Döcke et al., 1997b; unpublished observations).

These data suggest a close relationship between catecholamines and IL-10 release. However, it is not clear if catecholamines directly stimulate the IL-10 promoter in monocytic cells, the main cellular source of IL-10 in vivo (Jilg et al., 1996). Recently, we investigated four putative cAMP responsive elements (CRE) in the enhancer upstream of the IL-10 promoter. Two of them were shown to be involved in cAMP-activated IL-10 expression. Furthermore, our studies revealed the major role of CRE4, localized proximal to the transcription start site, in mediating the stimulatory effect of cAMP (Platzer et al., 1999).

Using transient transfection assays and gel shift analysis here we show that epinephrine and norepinephrine directly induce IL-10 expression mainly via the β2-adrenoreceptor cAMP-dependent signaling pathway and CRE4.

Section snippets

Cells, plasmids, transient transfection and reporter gene assay

THP-1 cells were maintained in RPMI 1640 with 10% FCS certified for low endotoxin and free of mycoplasma (Biochrom, Berlin, Germany). Cloning of the IL-10 promoter/enhancer fragment (GenBank accession No. Z30175) (Platzer et al., 1994) upstream of the luciferase gene (pGL2-basic from Promega to give pGL2-1308), in vitro mutation of CRE4 (mutCRE4) and transfections by electroporation were performed as described (Platzer et al., 1999). Transfected cells were cultured (1×106/ml) with dbcAMP

Catecholamines stimulate the IL-10 promoter/enhancer in a dose dependent fashion

Monocytes/macrophages are the main cellular source of IL-10 in vivo. Consequently, to investigate the mechanism of catecholamine-induced IL-10 we used the monocytic cell line THP-1. Transient transfection of THP-1 cells with the plasmid containing the native IL-10 promoter/enhancer (pGL2-1308) and subsequent luciferase assays provided evidence for its direct activation by epinephrine and norepinephrine in a concentration-dependent manner (Fig. 1A and B). Mean peak stimulation by a factor of 10

Discussion

The relationship between sympathetic nervous system activation and the regulatory effect of catecholamines on immunocompetent cells, mainly targeting monocytes/macrophages and T-cells, is a well studied phenomenon (Suberville et al., 1996, Van der Poll et al., 1996, Van der Poll and Lowry, 1997, Kavelaars et al., 1997, Hasko et al., 1998, Siegmund et al., 1998). Experiments with dopamine β-hydroxylase deficient mice demonstrated that physiological catecholamine production although not required

Acknowledgements

This work was supported by a grant from the Deutsche Forschungsgemeinschaft to C.P. Pl 163/4-2.

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