Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-α production by α2- and β-adrenoceptors in mice

doi:10.1016/S0165-5728(99)00234-9

Journal of Neuroimmunology

Volume 103, Issue 1, 1 February 2000, Pages 34-40

https://doi.org/10.1016/S0165-5728(99)00234-9 Get rights and content

Abstract

In the present study, the regulation of tumor necrosis factor-α (TNF-α) production by α₂- and β-adrenoceptors located on noradrenergic nerve terminals and on macrophages was studied in endotoxaemic mice. We found that reduction of the sympathetic outflow by reserpine dramatically increased the lipopolysaccharide (LPS)-induced TNF-α production, demonstrating that the release of endogenous noradrenaline (NA), controlled by presynaptic α₂-adrenoceptors, was a determinant factor in this model. By using α₂- and β-adrenergic drugs (clonidine, CH-38083, isoproterenol, propranolol) we provided the first in vivo evidence that, beside the dominance of neuronal α₂- and macrophage β-adrenoceptors, the α₂-adrenoceptors on macrophages were also involved in the modulation of LPS-induced TNF-α production. Since adrenergic drugs are widely used in the clinical practice, our findings may have therapeutical implications.

Introduction

The sympathetic nervous system innervates the primary and secondary immune organs providing them both systemically and in situ with its neurotransmitters (Felten and Olschkowa, 1987; Felten et al., 1987). Expression of α₂- and β-adrenoceptors were reported on macrophages (Abrass et al., 1985; Spengler et al., 1990), which can be activated by the endogenous ligand noradrenaline (NA), released from noradrenergic varicosities, and by adrenergic drugs used frequently in the clinical practice. The levels of NA, adrenaline, and dopamine, the principal transmitters of the sympathetic nervous system might be elevated due to infections (Hall and Hodge, 1971; Besedovsky et al., 1975) thus, they are able to regulate cytokine production (Hall and Hodge, 1971; Besedovsky et al., 1975; del Rey et al., 1981; Koff et al., 1986; Pastores et al., 1996; Vizi, 1998; Straub et al., 1998).

NA and the adrenergic drugs may influence the immune response directly, through the adrenergic receptors expressed on macrophages, and also on other immunologically competent cells and indirectly via alteration of the endogenous NA level by influencing the activity of release-regulating presynaptic α₂-adrenoceptors located on sympathetic nerve terminals (Elenkov and Vizi, 1991; Vizi, 1998; Vizi et al., 1986, Vizi et al., 1991). As was shown earlier (Haskó et al., 1995), boosting by CH-38083, a highly selective α₂-adrenoceptor antagonist (Vizi et al., 1986), the activation of the sympathetic outflow (by inhibiting the negative feed-back modulation) resulted in a reduction of LPS-induced TNF-α response in mice. Since the contribution and significance of differently localized adrenoceptors in the modulation of cytokine production has not yet been clarified, the aim of the present study is to investigate the role of α₂- and β-adrenoceptors both on the noradrenergic nerve terminals and on the macrophages in the regulation of the production of an inflammatory cytokine, TNF-α.

Section snippets

Animals

Male Crl:NMRI BR mice were purchased from Charles River Laboratories (Budapest) and kept in individual cages in the Animal Unit for at least 7 days before use. Animals received food and water ad libitum, and lighting was maintained on a 12-h cycle. All procedures were approved by the local ethical committee of the Institute.

Experimental design

One day before the experiment, mice were weighed and placed in individual cages in the experimental room. On the day of experiment animals were injected intraperitoneally

Effect of the α₂-adrenoceptor agonist clonidine on the LPS-induced TNF-α production

Pretreatment of animals with the selective α₂-adrenoceptor agonist clonidine 30 min prior to LPS injection significantly enhanced the LPS-evoked TNF-α response (Fig. 1). To examine whether the effect of clonidine is mediated through α₂-adrenoceptors, we administered the selective α₂-adrenoceptor antagonist CH-38083 (Vizi et al., 1986) to another group of animals 30 min before clonidine-treatment. The stimulatory effect of clonidine was completely abolished by CH-38083 and the TNF-α production

Discussion

Communication between the neuroendocrine and immune systems involves the concerted interplay of the release of mediators from both systems, including cytokines and neurotransmitters. Endogenous NA release is strongly elevated both by experimentally induced (Zhou and Jones, 1993) and by natural (Akiyoshi et al., 1990; Shimizu et al., 1994) immune reactions. Since sympathetic nerve terminals in the lymphoid organs are equipped with release-regulating presynaptic α₂-adrenoceptors that mediate

Acknowledgements

This work was supported by the following grants: to J.Sz. from the Hungarian Research Fund (OTKA No. T029233) and to E.S.V. from the Scientific Committee of the Ministry of Health (ETT No. 463/98) and from Hungarian Academy of Sciences (AKP No. 98-112 3,2).

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Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-α production by α2- and β-adrenoceptors in mice

Abstract

Introduction

Section snippets

Animals

Experimental design

Effect of the α2-adrenoceptor agonist clonidine on the LPS-induced TNF-α production

Discussion

Acknowledgements

Biochem. Biophys. Res. Comm.

Neuropharmacology

J. Neuroimmunol.