Adrenergic mechanisms in multiple sclerosis: the neuro–immune connection?

The role of adrenergic mechanisms in the modulation of the immune response is well established [1], and several lines of evidence point to their involvement in immunemediated diseases of the nervous system such as multiple sclerosis (MS) [2]. Adrenoceptor ligands such as the b-adrenoceptor agonists terbutaline and isoproterenol [3] and the a-adrenoceptor antagonist prazosin [4] produce beneficial results in rats with experimental allergic encephalomyelitis (EAE), an established animal model of MS. Nonetheless, the rational basis for a therapeutic role of adrenoceptor ligands in MS has been hampered by the limited comprehension of the contribution of such mechanisms to human disease. The interesting article by De Keyser and co-workers, published recently inTiPS [5], discussed the involvement of b2-adrenoceptors expressed on astrocytes in inflammatory demyelinationandaxonaldegeneration inMS,andprovides novel insights into this intriguing topic. In this regard, we would like to add further points for consideration. First, noradrenaline acting on b2-adrenoceptors on astrocytes might be derived not only from noradrenergic nerve endings but also from activated lymphocytes infiltrating the CNS. Human peripheral lymphocytes express, following their activation, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and subsequently increase their intracellular content of dopamine, noradrenaline and adrenaline by up to 20–40-fold basal levels [6]. Intracellular catecholamines that accumulate in activated lymphocytes appear to be involved in the modulation of activationinduced apoptosis [7]. In addition, they provide these cells with a supply of mediators to be released following appropriate stimulation. Interestingly, interferon b (IFN-b), which is at least partially beneficial in MS, appears to be a strong inducer of catecholamine production and release from activated lymphocytes [8]. Although the relevance of this in vitro effect for the in vivo activity of IFN-b remains to be established, it cannot be excluded that this might contribute to a ‘restorative’ effect by IFN-b of the astrocyte–lymphocyte crosstalk. It would therefore be of interest to investigate the effects of IFN-b on b-adrenoceptor expression on astrocytes. Second, human lymphocytes express adrenoceptors, which might represent additional targets for noradrenaline, either released by nerve endings or derived from immune cells. In patients with MS, b2-adrenoceptor expression on lymphocytes: (i) is increased; (ii) correlates withmagnetic resonance imaging (MRI) disease activity in primary progressive MS; and (iii) also occurs in the secondary progressive form of MS (although no relationship withMRI disease activity has been demonstrated) [9]. Increased production of cAMP has been detected in resting, but not activated, lymphocytes from MS patients following stimulation in vitro with b2-adrenoceptor agonists [10]. However, despite this phenomenon, reduced immunological responses to b2-adrenoceptor agonists appear to characterize lymphocytes from MS patients and from mice affected by EAE [11,12]. Biochemical deficiencies downstream of cAMP might therefore account for the aberrant signalling through b2-adrenoceptors in MS and EAE diseases, although these remain to be clearly elucidated [12]. The observation that IFN-b counteracts activation-induced reduction of b-adrenoceptor agonistinduced cAMP accumulation in human lymphocytes [13] might have interesting implications. It can therefore be proposed that in MS b2-adrenoceptor-dependent cAMP signalling might play a role not only in astrocytes, as pointed out by De Keyser and co-workers [5], but also in lymphocytes. In addition to b2-adrenoceptors, lymphocytes express a wide array of other G-proteincoupled receptors that, following stimulation, might Corresponding author: Marco Cosentino (marco.cosentino@uninsubria.it). Available online 8 May 2004 Update TRENDS in Pharmacological Sciences Vol.25 No.7 July 2004 350