Short CommunicationFunctional α1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis
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
References (23)
- et al.
General and segmental reduced pain thresholds in juvenile chronic arthritis
Pain
(1995) - et al.
Cross-regulation between G-protein-coupled receptors. Activation of β2-adrenergic receptors increase α1-adrenergic receptor mRNA levels
J. Biol. Chem.
(1991) - et al.
Adrenoceptor function in atopic dermatitis: in vitro and in vivo demonstrations
Acta Derm.-Venereol.
(1985) - Arnason, B.G.W. (1993) The sympathetic nervous system and the immune response. In: ed. P. Low, Clinical Autonomous...
- et al.
Beta-adrenergic receptors in lymphocyte subpopulations
J. Allergy Clin. Immunol.
(1980) - Blake, D.R., Unsworth, J., Outhwaite, J.M., Morris, C.J., Merry, P., Kidd, B.L., Ballard, R., Gray, L. and Lunec, J....
- et al.
Prazosin, an α1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat
Proc. Natl. Acad. Sci. USA
(1985) - et al.
Demonstration that circulating human blood cells have no detectable alphal-adrenergic receptors by ligand binding analysis
J. Allergy Clin. Immunol.
(1984) - et al.
The development of classification criteria for children with juvenile rheumatoid arthritis
Bull. Rheum. Dis.
(1989) - et al.
Sympathetic overactivity in patients with chronic renal failure
New Engl. J. Med.
(1992)