IL‐10: a key regulator of allergic disease

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.