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The Role of Cytokines in Allergy

Chul Hee Lee, M.D.

ABSTRACT

Several pathophysiologic features of allergic inflammation, such as T_H differentiation, the regulation of IgE, eosinophilia, mast cell proliferation, and cellular recruitment, are regulated by various cytokines. It has been of particular interest to investigate the underlying mechanism in the preferential activation of TH2 cells by allergens. Although interleukin (IL)-4 is the major determinant of TH2 differentiation, the original cellular source of IL-4 and the nature of the interaction between IL-4 and TH2 differentiation remain unclear. Recent studies have demonstrated that the regulation of IgE depends primarily on the functional activities of IL-4, IL-13, and IFN-γ. Eosinophilia and an increased number of mast cells characterize allergic inflammation, which is a T cell-dependent process. IL-5 is the major chemotactic and activating factor of eosinophils. Mast cell proliferation results from several cytokines, including IL-3, IL-9, and IL-10. It has been suggested that, in the late phase reaction of allergic inflammation, proinflammatory cytokines released from mast cells, eosinophils, and TH2 cells enhance the expression of adhesion molecules and chemokines that further promote the allergic cellular milieu.

KEY WORDS：TH differentiation·IgE·Eosinophil·Mast cell·Cytokine.

INTRODUCTION

Over the last decade, there has been enormous growth in the body of knowledge regarding the biology of cytokines in IgE- mediated allergic inflammation. This body of information now provides a framework for our understanding of the pathogenesis of chronic allergies and may in the future lead to new th- erapeutic strategies in the management of allergic reactions.

This article will review several important concepts regarding the role of cytokines in allergic inflammation and will focus on TH2 differentiation, IgE production, major effector cells including eosinophils and mast cells, and cellular recruitment.

TH1 / TH2 differentiation and the regulation of IgE

One of the most important elements to clarify in understanding the causes of allergic disorders is the TH1/TH2 differentiation process that occurs in response to the allergens. Although genetic predisposition, the specific physiochemical nature of the offending allergen, different antigen-processing and pres-

entation pathways, the type of antigen-presenting cells, and other factors play important roles in TH1/TH2 differentiation,¹⁾ one of the most critical determinants of TH differentiation is the nature of the cytokine milieu in which the T lymphocytes are activated (Fig. 1).

It has been demonstrated in mice that there are at least two types of TH cells, each with different patterns of cytokine synthesis.²⁾ TH1 cells produce interleukin (IL)-2, tumor necrosis factor (TNF)-β, and interferon (IFN)-γ, which are key effector cells in cell-mediated immunity and delayed-type hypersensitivity reactions. TH2 cells, on the other hand, secrete IL-4, which stimulate IgE and IgG1 production, IL-5 (eosinophil-activating factor), IL-10, and IL-13, which together with IL-4 inhibit certain macrophage functions.³⁾⁴⁾ It has been shown recently that TH1 and TH2 cells also function in vivo. Although the source of several cytokines, such as IL-2, IL-6, IL-10 and IL-13, appear to be less limited in humans, there is a general agreement of the existence of human TH cells that are compa- rable to murine TH1 and TH2 cells.

The major determinant of TH2 differentiation is IL-4.⁵⁾⁶⁾ It has been demonstrated that concomitant exposure of T cell receptor transgenic mice to IL-4 and its relevant antigen induces an increase in the production of IL-4 but inhibits development of IFN-γ-producing TH1 lymphocytes.⁷⁾ However, the original source of the IL-4 responsible for TH2 differentiation is yet to be clearly defined.

It has been shown that, in contrast to IL-4, IL-12 induces an increase in the concentration of IFN-γ and a decrease in the concentration of IL-4.⁸⁾⁹⁾ In addition to IL-12 and IFN-γ, Department of Otorhinolaryngology-Head Neck Surgery, Seoul

National University, College of Medicine, Seoul, Korea Address correspondence and reprint requests to Chul Hee Lee, M.D., Department of Otorhinolaryngology-Head Neck Surgery, Seoul National University, College of Medicine, 28 Yongon- dong, Chongno-ku, Seoul 110-744, Korea

Tel：82-2-760-3646, Fax：82-2-745-2387 Accepted for publication on March 10, 1998

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IFN-α, transforming growth factor (TGF)-β, and IL-1α receptor antagonist (IL-1Ra) have been reported to promote the differentiation of allergen-specific T cells into the TH1 in- stead of TH2 phenotype.⁴⁾ Cytokines produced by TH1 and TH2

subsets also antagonize each other’s effector functions. TH2

cytokines, IL-4 and IL-10, inhibit a number of TH1 functions, such as the production of IFN-γ.¹⁰⁾ However, the TH1-inducing effects of IL-12 can be overcome with the additional presence of IL-4；thus the effects of IL-4 on undifferentiated TH0 cells become dominant.¹¹⁾ The net result is that, in a milieu in which allergic inflammation is present, increasingly extensive allergic responses against bystander antigens can be expected to develop.

Aside from B cell growth and stimulation, IL-4 stimulates the expression of major histocompatibility complex (MHC) class II antigen, B7.1 (CD80), B7.2 (CD86), CD40, surface IgM, and low affinity IgE receptor by B cells, enhancing the antigen-presenting capacity of B cells.¹⁾¹²⁾ IL-4 also induces a switch in the immunoglobulin isotype from IgM to IgE.¹³⁾¹⁴⁾ IgE production occurs after the IL-4-induced germ line transcription of ε-heavy chain constant region genes. Additionally, B cell activating cytokines, including TNF-α,¹⁵⁾ IL-2,¹⁵⁾ IL- 5,¹⁶⁾ and IL-6,¹⁷⁾ react synergistically with IL-4 in the stimulation of IgE secretion.

Evidence suggests that IL-4 regulates IgE synthesis through B lymphocytes, and the extent to which T-cell clones support IgE production is directly proportional to IL-4 production.¹⁸⁾ On the other hand, IFN-γ, IFN-α, TGF-β, IL-8, IL-12 and other cytokines have been shown to inhibit IL-4-induced IgE synthesis.¹⁹⁾ In addition to its effects on B cells, IL-4 also induces T-cell proliferation, though to a lesser extent than IL-2.

IL-4 directs the differentiation of uncommitted T-cell precursors toward TH2 differentiation. As well as by TH, IL-4 may be secreted by natural killer cells, mast cells, and basophils.

IL-13 has IL-4-like biological activities and is considered to have 30% homology to IL-4. IL-13 induces an IgE isotype switch and stimulates human B cell growth in allergic inflammation.¹⁾⁶⁾ Moreover, it also induces adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1, at the

sites of the allergic inflammation, thus contributing to the selective accumulation of eosinophils and lymphocytes. IL-13 is distinguished from IL-4 by different mechanisms of tran- scriptional regulation：IL-4 tends to be an earlier and more transient signal in comparison to IL-13. IL-13 is distinguished from IL-4 also by the absence of effects on T lymphocytes.

IFN-γ is an another critically important cytokine in the regulation of IgE synthesis.¹⁾ It functions as an inhibitor of allergic responses by inhibiting the IL-4-mediated expression of low-affinity IgE receptors and IgE isotype switch. The ability of T-lymphocyte clones to support IgE production is inversely proportional to their IFN-γ production, and clones producing both IL-4 and IFN-γ will support IgE production only in the presence of anti-IFN-γ antibodies.¹⁴⁾¹⁵⁾ A recent study has shown that allergen challenge in seasonal allergic rhinitis results in no increase in IFN-γ in nasal lavage fluids.²⁰⁾ Additional cytokines that have been reported to inhibit IL-4-induced IgE production are IL-12, TGF-β, and IL-8.²¹⁾²²⁾

Cytokine regulation of eosinophils

Eosinophils are major effector cells in allergic diseases. Eo- sinophilia is a T-lymphocyte-mediated response, as demonstrated by its absence in athymic or T-cell-depleted animals.¹⁾⁶⁾ In addition to TH lymphocytes, potentially more important sources of IL-4 and IL-5 in allergic inflammation may be eosinophils and mast cells. It has recently been reported that the discrepancy between the mRNA and protein expressions of IL-4 and IL-5 may be attributed to their granule storage in gr- anulocytes, while they are secreted by T cells.²³⁾

IL-5 is of particular interest because it is the most important eosinophilopoietin in allergic inflammation. IL-5 induces ma- turation of a homogeneous population of eosinophils when exposed to bone marrow precursors.²⁴⁾ In addition to stimulating eosinophil production, IL-5 acts as a chemoattractant to eosinophils, activates mature eosinophils, induces eosinophil secretion, and prolongs eosinophil survival by reducing apoptosis.²⁵⁾ Demonstrating the importance of IL-5, it has been shown that the expression of IL-5 mRNA in the nasal mucosa

Fig. 1. Major cytokines in allergic inflammation. TH0

cells differentiate into TH2 cells after allergen stimulation. IL-4 is a major cytokine of TH2 differentiation, while IL-2 and IFN-γ are the major inhibitors of TH2 differentiation. These two patterns of cytokines antagonize each other, to contribute to the production of TH2-derived cytokines in allergic inflammation. IL-4 and IL-13 are the major cytokines in IgE synthesis. IL-3 and IL-9 play key roles in mast cell growth and differentiation. IL-5 is particularly important for eosinophil dif- ferentiation, survival, and chemotaxis.

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of patients with perennial allergic rhinitis increases during natural allergen exposure.²⁶⁾

In addition to IL-5, two colony-stimulating factors, IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), contribute to eosinophil activity in allergic inflammation by prolonging eosinophil survival and generating activated, hypodense eosinophils. Recent study further supports the view that GM-CSF is a major cytokine in allergic airway disease.²⁰⁾ In this study, nasal lavage fluid levels of GM-CSF were shown to increase in subjects with allergic rhinitis but not in the subjects with the common cold. Additional studies using in situ hybridization have demonstrated that GM-CSF mRNA increases in the nasal mucosa of allergic rhinitis patients after allergen provocation in association with tissue eosinophilia.²⁷⁾ RAN-TES (regulated upon activation, normal T expressed and presumably secreted),²⁸⁾ macrophage inflammatory protein (MIP)-1α, monocyte chemotactic peptide (MCP)-3, eotaxin-A and other members of the chemokine family are also involved in tissue eosinophilia. Compared to resting eosinophils, cytokine-stimulated eosinophils bind to vascular endothelium more avidly, migrate more rapidly and produce higher levels of newly-synthesized mediators. GM-CSF stimulates stem cell proliferation and activates eosinophils to prolong their survival.²⁹⁾ The production of some chemokines, such as RANTES and eotaxin, by respiratory epithelial cells likely attracts critical effector cells such as eosinophils.³⁰⁾

Mast cell proliferation

As with elevated IgE concentrations and eosinophilia, an increase in the number of mast cells, which characterizes allergic diseases, is a T cell-dependent process. Mucosal mast cells (MCT) proliferate in allergic rhinitis under the influence of TH2 cytokines.³¹⁾ Mast cell proliferation results from the activities of several cytokines, including IL-3, IL-9, and IL-10.

Prolonged exposure of human bone marrow cells to IL-3 results in a predominance of mast cells. This IL-3-stimulated mast cell proliferation is inhibited by GM-CSF.³²⁾ IL-9 is a TH2 lymphocyte-derived T cell growth factor that has been found to function as a mast cell growth factor in mice.³³⁾ IL-10 is also a cofactor in mast cell proliferation.

In addition to those factors involved in mast cell proliferation, several cytokines have been shown to induce histamine release from basophils and possibly mast cells. These factors include IL-3 and several chemokines, including RANTES, MIP- 1α, MCP-1, MCP-3, and connective tissue activating peptide- III. Of these, MCP-1 and RANTES are the most effective histamine releasing factors.³⁴⁾³⁵⁾ IL-8 inhibits cytokine-mediated histamine release by basophils.³⁶⁾ Mast cell degranulation is the critical initiating event of acute allergic symptoms. A variety

of cytokines, including TNF-α, IL-4, IL-5, IL-6, TGF-β and IL-13, may be released from mast cells.³⁷⁾

Cytokines in chronic allergic inflammation

The mechanism that regulates the persistence of local tissue inflammation in chronic allergic diseases remains unclear. Ho- wever, several cytokine-related factors may play roles.⁶⁾ First, once initiated, a TH2 cell response inhibits the function and activation of TH1 cells. Cytokines such as IL-4 and IL-13 inhibit the development of TH1-delayed-type hypersensitivity responses and enhance the development of TH2 cells, thus po- larizing the T cell response.³⁷⁾ Second, the prolonged survival of inflammatory cells arising from reduced apoptosis at the inflamed sites may result in the establishment of chronic inflammation. Increased productions of GM-CSF and IL-5 likely contribute to decreased apoptosis of monocytes and eosinophils, respectively.³⁸⁾³⁹⁾ Eosinophil apoptosis has been shown to play an important role in the resolution of airway inflammation in asthma.⁴⁰⁾ Finally, recent studies on mononuclear cells from atopic asthma cases indicate that allergen-induced immunity activation, which gives rise to high concentrations of IL-2 and IL-4, alters the T cell response to glucocorticoid receptor binding affinity and steroid responsiveness.⁴¹⁾

Cytokines and late phase response (LPR)

The regulation of the LPR is becoming better understood.

One of the most important processes in regulating LPR is the production of cytokines. These cytokines include IL-4 (produced by mast cells), IL-3, IL-4, IL-5 and GM-CSF (produced by TH2 cells), and IL-6 (produced by epithelial cells). Indeed, in situ hybridization studies have demonstrated that mRNA expression is preferential to IL-4 and IL-5 during the late phase at 24 hours.²⁷⁾⁴²⁾ Elevations in IL-3 and GM-CSF expression have been also observed, with no increases in IL-2 or IFN-γ. Moreover, it has been found that a correlation exists between the expression of TH2 cytokine mRNA, particularly IL-5, and the number of EG2⁺ eosinophils and contribute to the development of LPR and tissue eosinophilia.

Upon stimulation with proinflammatory cytokines, endothelial cells express different families of adhesion molecules, starting an adhesion cascade that leads to the transendothelial migration of inflammatory cells.⁴³⁾ However, this process is not allergy-specific and has also been shown in viral rhinitis.⁴⁴⁾ Allergen exposure induces the expression of E-selectin in endothelial cells,and TNF strongly upregulates its expression.⁴⁴⁾⁴⁵⁾ Intercellular adhesion molecule (ICAM)-1 is upregulated by IL-1β, TNF-α, and IFN-γ.⁴⁵⁾ When stimulated by cytokines such as IL-1, IL-4, IFN-γ, TNF-α, IL-5, and IL-13,⁴⁶⁾⁴⁷⁾ and

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chemokines such as RANTES⁴⁸⁾ and IL-8,³⁵⁾ endothelial cells become adhesive for eosinophils, basophils or neutrophils. The expression of adhesion molecules in epithelial cells rapidly increases following exposure to cytokines (IFN-γ or TNF- α).⁴⁹⁾ The release of TNF-α from mast cells promotes upregulation of leucocyte endothelial adhesion molecules E-selectin, ICAM-1, and VCAM-1.²⁹⁾ The release of mast cell IL-4 enhances the upregulation of VCAM-1, an adhesion molecule whose expression is evident in both perennial and seasonal allergic rhinitis.⁵⁰⁾ VCAM-1 upregulation enhances the adhe- siveness of endothelium for T cells, eosinophils, basophils, and monocytes but not for neutrophils, which is characteristic of allergic reactions. The corelease of IL-5 promotes eosinophil priming and chemotaxis.⁵¹⁾⁵²⁾ It has been suggested that, in the LPR of allergic inflammation, proinflammatory cytokines re-

leased from mast cells, eosinophils, and TH2 cells may enhance the expression of both adhesion molecules and chemoattract- ants to promote eosinophilic and basophilic infiltration.

CONCLUSION

Various cytokines regulate several pathophysiologic features of allergic inflammation, such as TH differentiation, the regulation of IgE, eosinophilia, mast cell proliferation, and cellular recruitment. Table 1 summarizes the specific role of allergy- related major cytokines. Of the pathophysiologic features of allergic inflammation, it is most important to understand the mechanism underlying the preferential activation of TH2 cells regulated by cytokines. Although IL-4 is the major determinant of TH2 differentiation, the original cellular source and genetic

Table 1. Cytokines and allergy

Cytokine Activity

TH1/TH2 differentiation IL Stimulates TH2 differentiation

IL Inhibits IL-4

IgE regulation IL-4, IL-13 ε isotype switching

IL-4 Generation of IL-4-producing T lymphocytes Synergize with IL-4, IL-13

IL-2, IL-5, IL-6 Inhibit IL-4, IL-13

IFN-γ, TGF-β Stimulates IFN-γ production by NK cells and T cells

IL-12 Inhibits differentiation of IL-4-producing T lymphocytes

Eosinophilia IL-5, IL-3, GM-CSF Eosinophilopoietins

RANTES, MIP-α, eotaxin, MCP-3 Eosinophil chemotaxis and activation IL-1, TNF Eosinophil activation

Mast cell development, IL-3, IL-9, IL-10 Mast cell growth factors

activations and GM-CSF Inhibits mast cell

proliferation MIP-1α, MCP-1 MCP-3, RANTES

Basophil chemotaxis and histamine release

IL-8 Inhibits histamine release

T-cell growth and activation IL-1, IL-2, IL-4, IL-5 IL-6, IL-7, IL-9, IL-11 IL-12, IL-15

T-cell growth factors

Inflammation IFN-γ, GM-CSF, TNFs IL-1, IL-4, IL-6, IL-8

Neutrophil activating factors GM-CSF, TNFs, IL-1,

IL-3, IL-5, RANTES

Eosinophil activating factors IFN-γ, GM-CSF, TNFs,

IL-1, IL-2, IL-3, IL-4

Macrophage activating factors

Anti-inflammatory IL-10, TGF-β Inhibit cytokine production, monocytes / T-cell functions

Adhesion molecule expression IL-1, TNF Express selectins, VCAM-1, and ICAM-1

IL-4 Expresses ICAM-1 and VCAM-1

IL-3, IL-5, IL-8 GM-CSF

Express integrins

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control of IL-4 remain unclear.

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