Inhibitory cytokines in asthma

doi:10.1016/S1357-4310(98)01335-5

Molecular Medicine Today

Volume 4, Issue 10, 1 October 1998, Pages 452-458

Molecular Medicine T...

https://doi.org/10.1016/S1357-4310(98)01335-5 Get rights and content

Abstract

Although research in asthma has concentrated on complex proinflammatory mechanisms, it is likely that defective expression of cytokines that inhibit allergic inflammation, such as interleukin 10, interleukin 12 and interferon γ, might also be important, particularly in determining disease severity and persistence of inflammation in the airways. Therapy based on these cytokines might also be useful, with the advantage that it restores the balance of endogenous cytokines. We discuss the therapeutic potential of these and other inhibitory cytokines in the treatment of asthma, particularly in patients with severe disease that is poorly responsive to conventional therapy, or as a disease-modifying treatment when used early.

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

•
Is a deficiency in inhibitory cytokines contributing to the severity of asthma and the persistence of asthmatic inflammation?
•
Is interleukin 10 (IL-10) effective in controlling asthma, particularly in patients who are not very responsive to corticosteroids?
•
Will IL-12 and interferon γ (IFN-γ) suppress airway inflammation in asthma?
•
Can IL-12 be used in combination with common allergens to provide specific immunotherapy to prevent the development of allergic asthma?
•
Will it be possible to develop

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Asthma, a complex airway inflammatory disease, is characterized by bronchoconstriction, AHR and airway remodelling [50]. Current consensus suggests that TH2 cytokine producing T cells, mast cells, and ASM cells play central roles in the pathogenesis of asthma [51]. This classification of asthma has led to the concept that the immediate response after allergen challenge is mediated by mast cells, whereas eosinophils are the predominant effector cells in the late asthmatic reaction [27].
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Allergic asthma is a chronic inflammatory condition of the lung characterized by reversible airway obstruction, high serum immunoglobulin (Ig) E levels, and chronic airway inflammation. A number of cells including mast cells, T cells, macrophages and dendritic cells play a role in the pathogenesis of the disease. Janus kinase (JAK)-3, a non-receptor protein tyrosine kinase, traditionally known to mediate cytokine signaling, also regulates functional responses of these cells. In this review the role of JAK-3 in regulating various pathogenic processes in allergic asthma is discussed. We propose that targeting JAK-3 is a rationale approach to control the inflammatory responses of multiple cell types responsible for the pathogenesis of allergic asthma.
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Asthma and chronic obstructive pulmonary disease (COPD) are both highly complex conditions whose pathobiology remains inadequately defined. In both diseases there are many different and distinct inflammatory cells and multiple mediators with complex acute and chronic effects on the airways and airspaces. The understanding of asthma pathogenesis has been enhanced by the application of new molecular, cell biological, and genetic techniques to the condition, and the key test of the acquired knowledge is the success of new specifically targeted therapies. In this area the successes have been few in asthma and are virtually absent in COPD. Although it is recognized that chronic inflammation underlies the clinical syndromes, it has been hard to define the precise nature of this inflammation, much less its primary etiology. Nevertheless it is appreciated that the final consequence of this chronic inflammatory response is an abnormal control of airway caliber in vivo in asthma. In contrast, the evolution of understanding in COPD has been much slower; key insights are sought which will open up the understanding of this complex disorder. It has also been possible to examine the airways of asthmatic patients by fiberoptic and rigid bronchoscopy, bronchial biopsy, and bronchoalveolar lavage (BAL). Direct bronchoscopic examination reveals that the airways of asthmatic patients are often erythematous and swollen, indicating acute inflammation.
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Asthma and chronic obstructive pulmonary disease (COPD) are both highly complex conditions whose pathobiology remains inadequately defined. In both diseases there are many different and distinct inflammatory cells and multiple mediators with complex acute and chronic effects on the airways and airspaces. The understanding of asthma pathogenesis has been enhanced by the application of new molecular, cell biological, and genetic techniques to the condition, and the key test of the acquired knowledge is the success of new specifically targeted therapies. In this area the successes have been few in asthma and are virtually absent in COPD. Although it is recognized that chronic inflammation underlies the clinical syndromes, it has been hard to define the precise nature of this inflammation, much less its primary etiology. Nevertheless it is appreciated that the final consequence of this chronic inflammatory response is an abnormal control of airway caliber in vivo in asthma. In contrast, the evolution of understanding in COPD has been much slower; key insights are sought which will open up the understanding of this complex disorder. It has also been possible to examine the airways of asthmatic patients by fiberoptic and rigid bronchoscopy, bronchial biopsy, and bronchoalveolar lavage (BAL). Direct bronchoscopic examination reveals that the airways of asthmatic patients are often erythematous and swollen, indicating acute inflammation.

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¹: DM, DSc, FRCP Head of Respiratory Science

²: MD Clinical Research Fellow

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Inhibitory cytokines in asthma

Abstract

Section snippets

Endogenous inhibitory mechanisms in asthma

Interleukin 10

IL-1 receptor antagonist

Interferon γ

Interleukin 12

Interleukin 18

Interleukin 4 and interleukin 13

Transforming growth factor β (TGF-β)

Future directions

Glossary

The outstanding questions

Immunol. Today

J. Biol. Chem.

J. Allergy Clin. Immunol.

Lancet

Gastroenterology

J. Allergy Clin. Immunol.

Cytokine

J. Allergy Clin. Immunol.

J. Allergy Clin. Immunol.

Blood

Clin. Immunol. Immunopathol.

Immunity

Immunol. Today

Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases

New Engl. J. Med.

Interleukin-10 and its receptor

Ther. Immunol.

IgE versus IgG4 production can be differentially regulated by IL-10

J. Immunol.

Regulation of interleukin-1 receptor antagonist by Th1 and Th2 cytokines

Am. J. Physiol.

Interleukin-10 inhibits cytokine generation from mast cells

Eur. J. Immunol.

Human airway smooth muscle cells express and release RANTES in response to Th1 cytokines: regulation by Th2 cytokines

J. Immunol.

The orphan receptor CRF2–4 is an essential subunit of the interleukin 10 receptor

J. Exp. Med.

Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice

J. Clin. Invest.

Inhaled corticosteroids increase IL-10 but reduce MIP-1α, GM-CSF and IFN-γ release from alveolar macrophages in asthma

Am. J. Respir. Crit. Care Med.

Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma

Eur. Respir. J.

An investigation of polymorphism in the interleukin-10 gene promoter

Eur. J. Immunogenet.

Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers

Clin. Pharmacol. Ther.