Short Communication
Functional α1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis

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Abstract

During the last decade it has been shown that the central nervous system can influence the immune system. In healthy individuals, catecholamines can inhibit the production of pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) via interaction with β2-adrenergic receptors. In contrast, we show here that catecholamines can stimulate the production of the interleukin-6 (IL-6) in children with the chronic inflammatory disease polyarticular juvenile rheumatoid arthritis (JRA). The induction of IL-6 is mediated by triggering of α1-adrenergic receptors on peripheral blood leucocytes of the patients with polyarticular JRA. Functional α1-adrenergic receptors are absent on leukocytes of normal donors and on leukocytes of patients with the oligoarticular form of the disease.

Introduction

Juvenile rheumatoid arthritis (JRA) is a chronic inflammatory joint disease. The oligoarticular form of the disease is characterized by inflammation of less than four joints, whereas polyarticular JRA is characterized by an inflammation of five or more joints. Moreover, in 50–70% of the patients with oligoarticular JRA the disease goes into complete remission, whereas the prognosis for children with the polyarticular form of the disease is worse. In only 20% of the patients with polyarticular JRA the disease goes into complete remission (Gare and Fasth, 1995).

The disease JRA is associated with clinical symptoms of altered functioning of the autonomous nervous system such as increased perspiration, increased micturition, sleep disturbances and a decreased pain threshold (Kuis and Heijnen, 1994; Hogeweg et al., 1995). Recently, we showed that children with JRA have an increased urinary level of the noradrenergic metabolite 3-methoxy-4-hydroxy-phenyl-glycol (MHPG) (Kuis et al., 1996). This is indicative for an increase in the central noradrenergic outflow which will lead to increased vasoconstriction. Due to the increased vasoconstriction, patients with JRA, have diminished catecholamine and cardiovascular responses to orthostatic stress (Kuis et al., 1996).

In general the central autonomic outflow from the pons and medulla to the spinal cord activates sympathetic nerve fibers innervating lymphoid organs (Felten et al., 1987). Activation of sympathetic fibers results in secretion of catecholamines which, under normal conditions, leads to a modulation of the ongoing immune response via binding to either β2- or α2-adrenergic receptors (Crary et al., 1983; Arnason, 1993; Bisphoric et al., 1980; Severn et al., 1992; Spengler et al., 1994). Spengler et al., have shown, that in vivo activated peritoneal murine macrophages express α2-adrenergic receptors. Activation of these receptors leads to an upregulation of lipopolysaccharide (LPS)-induced TNF-α production (Spengler et al., 1994). Culture of human monocytes with adrenaline and LPS leads to inhibition of TNF-α production via β2-adrenergic receptors (Severn et al., 1992). Peripheral blood leukocytes of healthy individuals do not express α1-adrenergic receptors (Cassale and Kaliner, 1984). However, we show here that peripheral blood mononuclear cells (PBMC) of patients with polyarticular JRA respond to α1-adrenergic activation with an increased production of the pro-inflammatory mediator IL-6.

Section snippets

Patients and methods

We studied 8 patients with oligoarticular JRA and 12 patients with polyarticular JRA, defined by the criteria of the American College of Rheumatology (ACR) (Cassidy et al., 1989). Characteristics of the patients are summarized in Table 1. Healthy adult volunteers from our department were taken as controls.

PBMC were isolated from heparinized blood by Ficoll Isopaque density gradient centrifugation (Pharmacia, Uppsala, Sweden). Cells (1 × 106/ml) were cultured in flat-bottom 24-well plates in

Results and discussion

Basal IL-6 production determined in culture supernatants of PBMC without stimulus did not differ between patients and controls [oligoarticular JRA patients (n = 8), 643 ± 382 pg/ml; polyarticular JRA patients (n = 12), 678 ± 192 pg/ml; controls (n = 10), 856 ± 275 pg/ml; mean ± sem, F(2,27) = 0.17, p > 0.8]. To investigate whether the leukocytes of patients can respond to α-adrenergic activation, the effect of the α-adrenergic agonist phenylephrine on the production of IL-6 was tested. Culture

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