In a double-blind randomized study, we compared the effects of the M1-selective muscarinic receptor antagonists pirenzepine and the nonselective antagonist ipratropium bromide on bronchoconstriction induced by inhaled sulfur dioxide (SO2) and methacholine in atopic volunteers. Both inhaled pirenzepine (70 µg) and ipratropium bromide (7 µg) significantly inhibited vagally mediated bronchoconstriction by SO2 to the same extent (p < 0.02). However, at this dose, pirenzepine had no effect on methacholine-induced bronchoconstriction, whereas ipratropium bromide gave significant protection (p < 0.02). This indicates that vagaily mediated bronchoconstriction in humans can be inhibited by blockade of pirenzepine-sensitive (M1) muscarinic receptors probably present on a different site from muscarinic receptors at the neuromuscular junction and presumably localized to parasympathetic ganglia. Pirenzepine may be useful in investigating ganglionic function and could be beneficial therapeutically in airway disease.
No abstract is provided for this article.
No abstract is provided for this article.
IL-10 is a unique cytokine with a wide spectrum of anti-inflammatory effects, with a profile of activity that suggests that it may be a powerful inhibitor of allergic responses. IL-10 is produced by several cell types, including monocytes, macrophages, T lymphocytes, dendritic cells, mast cells [1,2]. IL-10 acts on specific IL-10 receptors, that have now been cloned, although the signal transduction pathways and kinases that lead to the widespread anti-inflammatory actions of this cytokine are not yet well understood. Some of the actions of IL-10 can be explained by an inhibitory effect on the transcription factor nuclear factor-κB (NF-κB) [3], but this does not account for all effects as IL-10 is very effective at inhibiting IL-5 transcription which is independent of NF-κB [4]. In mice many effects of IL-10 appear to be mediated by an inhibitory effect on phosphodiesterase (PDE)-4, but this does not appear to be the case in human cells [5]. IL-10 has a very broad spectrum of anti-inflammatory and anti-allergic effects. It inhibits the synthesis of proinflammatory cytokines (IL-1β, tumour necrosis factor-alpha (TNF-α), IL-6), and the Th2 cell-derived cytokines IL-4 and IL-5 [1,4,6]. IL-10 also inhibits chemokines such as MIP-1α, RANTES, IL-8 and eotaxin [7–10]. IL-10 also inhibits the expression of the inflammatory enzymes inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in macrophages [11,12]. Thus IL-10 has the capacity to inhibit the expression of many of the inflammatory genes that are abnormally expressed in allergic diseases. It also inhibits the proliferation of CD4+ T lymphocytes by inhibiting IL-2 release and reduces expression of MHC class II molecules, the costimulatory molecules B7-1 and B7-2 and low-affinity IgE receptors (CD23) in antigen-presenting cells, thus effectively blocking allergen presentation by mononuclear cells and dendritic cells to T cells [13]. In addition, IL-10 also increases the expression of several anti-inflammatory proteins, including IL-1 receptor antagonist [14] and tissue inhibitor of matrix metalloproteinases [15]. IL-10 inhibits the release of cytokines from several cell types, including proliferating airway smooth muscle cells [9,10]. It is very effective in inhibiting eosinophilic inflammation in animal models and this may be through its combined inhibitory effects on IL-5 synthesis, the release of eosinophilotactic chemokines (such as eotaxin and RANTES) and through a reduction in eosinophil survival, probably as a result of decreased granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion [16]. In this issue of the journal, Royer et al. demonstrate that IL-10 also has an inhibitory effect on IgE-dependent activation of human lung mast cells, with inhibition of TNF-α and IL-8 [17]. Surprisingly (and in contrast to results in rodent mast cells), IL-10 also inhibits the release of histamine, suggesting an inhibitory effect on degranulation. A blocking antibody to IL-10 increases the release of cytokines from monocytes and macrophages, suggesting that IL-10 may serve as an endogenous feedback inhibitory mechanism to damp down the inflammatory response [13]. This has also been demonstrated in vivo in a murine model of allergic inflammation, where an IL-10 blocking antibody increases the airway inflammatory response to allergen [18]. Similarly, IL-10 gene knock-out mice have an increased eosinophilic inflammatory response to allergen [19]. The kinetics of IL-10 production show a late secretion, which is not maximal until 24 h after stimulation, whereas the inflammatory genes suppressed by IL-10 are much more rapidly expressed (6–12 h). This suggests that IL-10 may function as a late ‘braking’ mechanism that prevents persistence of the inflammatory response. There is increasing evidence that IL-10 secretion may be defective in patients with asthma [20,21]. Lower concentrations of IL-10 are found in bronchoalveolar lavage fluid of asthmatic patients than in normal control subjects [22] and there is a reduction in the number of macrophages expressing IL-10 in induced sputum [23]. There is a reduced secretion of IL-10 from alveolar macrophages obtained by bronchoalveolar lavage from asthmatic patients compared with normal controls, and this is at the level of gene expression [24]. This reduced expression of IL-10 is correlated with an increase production of proinflammatory cytokines, such as TNF-α and GM-CSF, and the chemokine MIP-1α. This suggests that a defect in IL-10 synthesis may result in exaggerated and more prolonged inflammatory responses in asthmatic airways. Furthermore, since IL-10 appears to act as a feedback inhibitor of antigen presentation by mononuclear cells, this may also account for the observation that macrophages from asthmatic patients are less effective at inhibiting T cell proliferative responses [25]. The production of IL-10 from peripheral blood monocytes is reduced in allergic compared with normal subjects after influenza A infection, suggesting an impaired ability to mount an anti-inflammatory response in allergy [26]. IL-10 levels are reported to be normal in patients with mild asthma, however, [27] and IL-10 release from peripheral blood monocytes is increased during the late response to allergen [28]. The gene for IL-10 has been mapped to chromosome no. 1 and several polymorphisms in the 5′-promoter region of the IL-10 gene have been identified that are associated with altered synthesis of IL-10 in response to inflammatory stimuli [29]. These polymorphisms are not associated with the prevalence of asthma, but a haplotype that results in reduced IL-10 synthesis is found significantly more often in patients with severe asthma, who require high doses of inhaled or oral corticosteroids for control [30]. A similar association has recently been reported in rheumatoid arthritis with a more severe form of the disease [31]. This suggests that IL-10 may play a key role in determining disease severity and that this may be genetically determined. A polymorphism in the IL-10 promoter has also been associated with increased levels of total IgE [32]. The potent immunosuppressive and anti-inflammatory action of IL-10 has suggested that it may be useful therapeutically in the treatment of allergic diseases [33]. There are theoretical reasons why IL-10 itself may not be suitable as a treatment, since it suppresses the production of IL-12 and interferon-gamma (IFN-γ), thus favouring the predominance of Th2 cells. However, its powerful anti-inflammatory effects appear to more than compensate for any tendency to increase eosinophilia, so that in animal studies it is very effective at blocking eosinophilic inflammation. Recombinant IL-10 (given intranasally) is effective in suppressing allergen inflammation in a murine model [18]. Recombinant human IL-10 has been given to healthy volunteers by subcutaneous injection and is reasonably well tolerated, with a reduction in lipopolysaccharide (LPS)-induced IL-1β and TNF-α release from whole blood ex vivo[34]. In the future it may be possible to deliver IL-10 by a transgene adenovirus vector which results in more prolonged production of IL-10 [35]. Another approach to increase IL-10 production is to increase its synthesis. Treatment with inhaled corticosteroids restores the abnormally low production of IL-10 from alveolar macrophages and concomitantly reduces the release of inflammatory cytokines [24]. Similarly, therapeutic concentrations of theophylline increase IL-10 production from monocytes and this may underlie the recently recognized immunomodulatory and anti-inflammatory action of this drug [36]. Theophylline may be effective by inhibition of phosphodiesterase (PDE), thus increasing intracellular cyclic AMP concentrations. In mononuclear cells PDE inhibitors increase IL-10 release [37], although this does not appear to be the mechanism for inhibiting TNF-α release [5]. Another possibility for therapy in the future is the development of other agonists for the IL-10 receptor, or drugs that activate the unique, but so far unidentified, signal transduction pathways activated by this cytokine.
No abstract is provided for this article.
