Inhibitory cytokines in asthma
Section snippets
Endogenous inhibitory mechanisms in asthma
Although multiple proinflammatory mediators have been implicated in asthma, relatively few mechanisms that inhibit the inflammatory process have been identified. Potential endogenous mechanisms in asthma include cortisol, prostaglandin E2, vasoactive intestinal peptide (VIP) and adrenomedullin (Appendix A). There is increasing evidence that certain cytokines have anti-inflammatory or immunomodulatory effects and that their secretion might be defective in asthmatic patients. This review
Interleukin 10
IL-10 is a 36 kDa homodimeric cytokine that was originally identified as a product of murine Th2 lymphocyte clones that suppressed the synthesis of cytokines from Th1 cells and was termed cytokine synthesis inhibitory factor. IL-10 is produced by several cell types, including Th1 and Th2 cells, mast cells and dendritic cells, but in lungs the major cellular source is the macrophage[3].
IL-1 receptor antagonist
IL-1ra is produced by monocytes, macrophages and epithelial cells in response to inflammatory stimuli[23]. It binds to the IL-1 receptor (IL-1R1) without signalling and thus inhibits the effects of IL-1α and IL-1β. IL-1ra inhibits the synthesis of IgE and inflammatory cytokines in human peripheral blood mononuclear cells stimulated with lipopolysaccharide[24]. Increased expression of IL-1ra has been reported in asthmatic airways[25]. In ovalbumin-sensitized guinea pigs, aerosolized IL-1ra
Interferon γ
IFN-γ is primarily released by T cells and NK cells. It is produced by Th1 cells and has an inhibitory effect on Th2 cells, thus reducing the synthesis of IL-4 and IL-5. In mice, aerosolized IFN-γ inhibits allergen-induced eosinophilic inflammation in the lungs, whereas targeted disruption of the IFN-γ receptor gene results in a prolonged airway eosinophilia in response to allergen[27]. Some of the effects of IFN-γ might be mediated by induction of the IL-10 gene. IFN-γ also inhibits IL-4
Interleukin 12
IL-12 is a heterodimer composed of two covalently linked proteins (p40 and p35) that are encoded by separate genes[34]. It acts on specific receptors that are expressed on T cells and NK cells. It is produced by antigen-presenting cells, including monocytes, macrophages and dendritic cells, and is upregulated by IFN-γ, TNF-β and GM-CSF. IL-12 plays a pivotal role in cell-mediated immunity. A major action of IL-12 is to induce the development of Th1 cells, while suppressing Th2 cells (Fig. 3).
Interleukin 18
IL-18 is an 18 kDa cytokine formerly known as IFN-γ-inducing factor, because it releases IFN-γ from T cells. It is structurally related to IL-1, but acts like IL-12 to promote Th1 cell development and to suppress Th2 cells, although it appears to act via distinct cell signalling pathways[46]. IL-18 is synthesized as a precursor that requires IL-1 converting enzyme (ICE) to release the active cytokine. IL-18 has similar biological effects to IL-12 and acts synergistically with it to increase
Interleukin 4 and interleukin 13
IL-4 is normally regarded as proinflammatory in asthma, since it is crucial for the development of Th2 cells and for IgE synthesis from B cells. Indeed, IL-4 antibodies and IL-4 soluble receptors are in development as potential anti-asthma treatments. However IL-4, and the related cytokine IL-13, also have anti-inflammatory effects. Both cytokines inhibit the gene expression of inflammatory cytokines, such as chemokines, TNF-α and IL-1β. For example, both cytokines inhibit the expression of
Transforming growth factor β (TGF-β)
TGF-β has highly complex effects, depending on the presence of other cytokines. TGF-β has multiple proinflammatory effects and promotes remodelling, but is also a potent immunosuppressant owing to direct inhibitory effects on Th cells and B cells[53]. However, TGF-β is unlikely to have any therapeutic potential in asthma, as the balance of its action seems to favour fibrosis in the airways.
Future directions
The recognition that several cytokines have inhibitory effects on allergic inflammation and that some of them (IL-10, IFN-γ, IL-12) might be deficient in asthma suggests that they have the potential to provide new and more-specific approaches to therapy. However, they would have to provide important advantages over existing anti-inflammatory therapy with inhaled corticosteroids, which is highly effective in the majority of patients with asthma and is easy to administer. There are two important
Glossary
Airway hyperresponsiveness—Increased responsiveness of the airway to many triggers and bronchoconstrictors, such as cholinergic agonists and histamine. It is the characteristic physiological abnormality of asthma and reflects eosinophilic inflammation of the airways.
Chemokines—Cytokines that are chemotactic for inflammatory cells and are involved in the recruitment of inflammatory cells to sites of inflammation.
Co-stimulatory molecules—Surface molecules that facilitate antigen presentation,
The outstanding questions
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Is a deficiency in inhibitory cytokines contributing to the severity of asthma and the persistence of asthmatic inflammation?
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Is interleukin 10 (IL-10) effective in controlling asthma, particularly in patients who are not very responsive to corticosteroids?
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Will IL-12 and interferon γ (IFN-γ) suppress airway inflammation in asthma?
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Can IL-12 be used in combination with common allergens to provide specific immunotherapy to prevent the development of allergic asthma?
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Will it be possible to develop
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