IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response
Susumu Nakae1,
Yutaka Komiyama1,
Hiroshi Yokoyama1,4,
Aya Nambu1,
Masaomi Umeda3,
Michiko Iwase2,
Ikuo Homma2,
Katsuko Sudo1,
Reiko Horai1,
Masahide Asano1,5 and
Yoichiro Iwakura1
1 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 2 Second Department of Physiology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan 3 Research Center Kyoto, Bayer Yakuhin, Ltd, 6-5-1-3 Kunimidai, Kizu-cho, Sorakugun, Kyoto 619-0216, Japan 4 Present address: Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 5 Present address: Institute for Experimental Animals, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan
Correspondence to: Y. Iwakura; E-mail: iwakura{at}ims.u-tokyo.ac.jp
Transmitting editor: S. J. Galli
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Abstract
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IL-1 is a pro-inflammatory cytokine consisted of two molecular species, IL-1
and IL-1ß, and the IL-1 receptor antagonist (IL-1Ra) is a natural inhibitor of both molecules. Although it is suggested that IL-1 potentiates immune responses mediated by Th2 cells, the role of IL-1 in asthma still remains unclear. In this study, we demonstrate that the ovalbumin (OVA)-induced airway hypersensitivity response (AHR) in IL-1
/ß-deficient (IL-1
/ß/) mice was significantly reduced from the levels seen in wild-type mice, whereas the responses seen in IL-1Ra/ mice were profoundly exacerbated, suggesting that IL-1 is required for Th2 cell activation during AHR. OVA-specific T cell proliferation, IL-4 and IL-5 production by T cells, and IgG1 and IgE production by B cells in IL-1
/ß/ mice were markedly reduced compared with these responses in wild-type mice; such responses were enhanced in IL-1Ra/ mice. Using IL-1
/ and IL-1ß/ mice, we determined that both IL-1
and IL-1ß are involved in this reaction. Both IgG1 and IgE levels were reduced in IL-1ß/ mice, while only IgE levels were affected in IL-1
/ mice, indicating a functional difference between IL-1
and IL-1ß. These observations indicate that IL-1 plays important roles in the development of AHR.
Keywords: IL-1 receptor antagonist, IL-1
, IL-1ß, knockout mouse
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Introduction
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Allergic asthma is a Th2 cytokine-mediated inflammatory response of the lungs characterized by mucus hypersecretion, airway inflammation and airway hyper-responsiveness to spasmogenic stimuli (1). In cases of asthma presenting with lung inflammation, the infiltration of eosinophils is predominant; the degree of infiltration correlates with illness severity (2). T cells, B cells and mast cells are also involved in the development of the allergic response, acting through the release of cytokines, antibodies and inflammatory mediators (1,3).
Allergen-specific Th2 cells function in the development of AHR by secreting cytokines, including IL-4, IL-5 and IL-13 (1). IL-4 and IL-13 are required for AHR induction through inducing allergen-specific IgG1 and IgE production (4), resulting in the activation of mast cells via antigen/antibody complexFc receptor signaling (5), while IL-5 demonstrates a critical role in eosinophilia (4,6). Activated mast cells produce IL-4, IL-5, tumor necrosis factor (TNF)-
and various inflammatory mediators within the inflammatory site (5). IL-4 and TNF-
can induce vascular cell adhesion molecule (VCAM)-1 expression on endothelial cells, leading to the adhesion of various inflammatory cells to local inflammatory sites (7,8).
IL-1, a pro-inflammatory cytokine involved in a variety of immune responses, can promote mast cell activation and production of Th2 cytokines (9,10), suggesting that IL-1 functions in the development of allergic diseases. It is also known that IL-1 is a potent inducer of VCAM-1 on vascular endothelial cells (1113) and mice lacking the type I IL-1 receptor (IL-1RI/ mice) exhibit reduced eosinophil recruitment into the lungs due to the decreased expression of VCAM-1 during antigen-induced AHR (14). Furthermore, IL-1 can activate Th2 cells and enhance antibody production (1520). The involvement of IL-1 in asthmatic diseases that are mediated by Th2 cells, however, remains unclear. It is also unknown if either IL-1
or IL-1ß or both are necessary for AHR development. In this study, we demonstrate that IL-1 is required for allergen-specific Th2 cell activation and that both IL-1
and IL-1ß function in the development of AHR.
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Methods
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Mice
IL-1
/, IL-1ß/, IL-1
/ß/ and IL-1Ra/ mice were generated by homologous recombination as described, then backcrossed to BALB/cA mice for eight generations (21). DO11.10 Tg mice (BALB/c background) were kindly provided by Dr Dennis Y. Loh (22). All mice were housed under specific pathogen-free conditions in an environmentally controlled clean room at the Center for Experimental Medicine, Institute of Medical Science, University of Tokyo. All experiments were conducted according to the institutional ethical guidelines for animal experiments and safety guidelines for gene manipulation. Sex- and age-matched adult mice aged 812 weeks old were used for experimentation.
Ovalbumin (OVA)/alum-induced airway hypersensitivity
Mice were actively sensitized by i.p. injection of 100 µg of OVA with aluminum potassium sulfate (alum) on days 0 and 14. They were challenged intranasally by 100 µg of OVA in 50 µl saline, using a microsyringe, on days 14, 21, 24 and 27. Sham-sensitized mice were treated with i.p. injections of alum precipitated with saline alone and intranasal doses of saline alone. Twenty-four hours after the last intranasal administration of OVA, mice were anesthetized with pentobarbital (80 mg/kg, i.p.) and i.v. access was established by cannulating the jugular vein. The trachea was cannulated and connected to a rodent ventilator (model 687; Harvard Apparatus, South Natick, MA) with air supplemented at a tidal volume of 100.8 ± 3.3 µl/10 g body wt (n = 24), frequency of 100 breaths/min and positive end-expiratory pressure of 3 cmH2O. After neuromuscular blockade with gallamine triethiodide (10 mg/kg, i.v.), bronchoconstriction was measured according to the overflow method, using a pressure transducer (7020; Ugo Basile, Milan, Italy) connected to the tracheal cannula. To assess the bronchial responsiveness to i.v. injected acetylcholine (ACh), the changes in the respiratory overflow volume were measured using progressively increasing doses of ACh. The increase in respiratory overflow volume provoked by ACh was represented as a percentage of the maximal overflow volume (100%) obtained by clamping the tracheal cannula.
OVA/PBS-induced airway hypersensitivity
OVA immunization without alum was performed as described previously (23,24). Briefly, mice were i.p. injected with 10 µg of OVA (grade II; Sigma, St Louis, MO) in 0.5 ml of PBS on each of 7 alternate days (one injection per day). Four weeks after the final immunization, mice were challenged intranasally 8 times for 8 days (one challenge per day) with 20 µl of either PBS alone as a control or PBS containing 100 µg of OVA. AHR to methacholine was assessed using the parameter Penh (enhanced pause), which is calculated automatically based on the mean pressure generated in plethysmograph chambers during inspiration and expiration with the Buxco system as described elsewhere (25). Twenty-four hours following the last inhalation of OVA, bronchial responses to aerosolized methacholine (Sigma) were measured using the Buxco system (Buxco Electronics, Sharon, CT).
OVA-specific T cell proliferation assay
To measure secondary T cell responses, submaxillary lymph nodes (LN) were harvested 24 h after the last challenge with OVA. Single-cell suspensions prepared from these samples were cultured in a 96-well flat-bottom plate at a concentration of 5 x 104 cells/well in the absence or presence of 40 µg/ml OVA for 72 h. The primary T cell response was measured using DO11.10 CD4+ T cells as described previously (26). The CD4+ T cells from DO11.10 Tg mice (5 x 105 cells/well) and Thy1.2B220 splenic adherent cells (1 x 104 cells/well) from either wild-type or IL-1-deficient mice were cultured in the absence or presence of 0.1 µM OVA323339 peptide for 72 h. Next, [3H]thymidine (0.25 µCi/ml) (Amersham, Little Chalfont, UK) was added to the culture. After a 6-h label, the cells were harvested using a Micro 96 cell harvester (Skatron, Lier, Norway). Incorporated [3H]thymidine was measured using the Micro Beta System (Pharmacia Biotech, Piscataway, NJ).
Detection of cytokine by ELISA
The Mini Kit mouse IL-4 kit (Endogen, Woburn, MA) for IL-4 and Titer Zyme EIA kit (PerSeptive Diagnostics, Cambridge, MA) for IL-5 were used to determine the cytokine levels according to the manufacturers protocol.
Detection of serum Ig
To detect either OVA-specific or total Ig levels by ELISA, 50 µl of either 10 µg/ml OVA or 10 µg/ml rabbit anti-mouse Ig (Dako, Glostrup, Denmark) was coated onto 96-well flat-bottom plates. Following blocking with 0.05% skim milk in PBS for 1 h, 50 µl of the test samples was added to each well. After extensive washing, 50 µl of either alkaline phosphatasegoat anti-mouse IgG1 (Zymed, San Francisco, CA) or alkaline phosphataserat anti-mouse IgE (Southern Biotechnology Associates, Birmingham AL) was added to visualize bound antibodies. Alkaline phosphatase activity was measured using Substrate Phosphatase SIGMA104 (Sigma).
Statistics
Students t-test was used for the statistical evaluation of the results.
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Results
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Involvement of IL-1 in AHR
Although eosinophil infiltration into the lungs decreases in IL-1RI/ mice on a 129 x B6 background (14), the involvement of IL-1 in the development of AHR remained to be studied. Thus, to determine whether IL-1 is necessary for the induction of AHR, we examined the role of IL-1 in this response using IL-1
/ß/ mice on a BALB/cA background following sensitization to OVA. First, we examined AHR induced by OVA/alum. Upon sensitization with OVA/alum, AHR in response to methacholine stimulation was not different between wild-type and IL-1
/ß/ mice (Fig. 1). Moreover, mutant mice immunized with OVA/alum exhibited a similar level of eosinophil infiltration into the lungs and similar IgE levels in sera as wild-type mice (data not shown).
Since we previously experienced that the function of IL-1 in the humoral immune response was substituted by other cytokines in the presence of adjuvant (18), we next examined AHR induced by OVA in the absence of alum. Twenty-four hours after the final OVA inhalation, AHR to methacholine in IL-1
/ß/ mice was significantly reduced compared with that observed in wild-type mice (Fig. 2). Consistent with the reduced AHR in IL-1
/ß/ mice, the number of lung-infiltrating cells in IL-1
/ß/ mice as revealed by the histology following OVA inhalation was less than that seen for wild-type mice (data not shown). The total cell numbers in the bronchoalveolar lavage of IL-1
/ß/ mice were decreased compared with that in wild-type mice (data not shown).
On the other hand, AHR to methacholine in IL-1Ra/ mice was markedly increased compared with the response seen in wild-type mice (Fig. 2B). As expected, the inflammatory responses observed in IL-1Ra/ mice given OVA were enhanced (data not shown). These results suggest that IL-1 functions in the development of AHR.
Roles of IL-1 in Th2 cell activation during AHR
Although IL-1 is thought to promote both Th1 and Th2 cell-mediated immune responses, the role of IL-1 in Th2 cell activation during AHR remains poorly understood (1520). Therefore, we assessed allergen-specific T cell responses in IL-1
/ß/ mice challenged with OVA. The OVA-specific T cell proliferative responses of IL-1
/ß/ mice were profoundly decreased in comparison with those in wild-type mice (Fig. 3A). The levels of the Th2 cytokines IL-4 and IL-5 were also reduced in the supernatants of the IL-1
/ß/ LN cell cultures (Fig. 3B). In contrast, OVA-specific proliferative responses and the production of IL-4 and IL-5 in LN cells increased in IL-1Ra/ mice (Fig. 3C and D). These results suggest that IL-1 plays an important role in Th2 cell activation during AHR.
Allergen-specific IgG1 and IgE production
The levels of OVA-specific IgG1 and IgE in sera were determined by ELISA to assess if reduced Th2 cell activation affected B cell antibody production in IL-1
/ß/ mice. OVA-specific IgG1 and IgE levels in sera obtained from IL-1
/ß/ mice were significantly lower than those seen in wild-type mice (Fig. 4A). Sera from IL-1Ra/ mice, however, contained elevated levels of IgG1 and IgE as compared to those from wild-type mice (Fig. 4B), suggesting that IL-1 is necessary for Th2 cytokine-dependent antibody production in AHR.
Roles of IL-1
and IL-1ß in AHR
To determine whether IL-1
or IL-1ß, or both, are involved in the development of AHR, we sensitized IL-1
/ and IL-1ß/ mice with OVA in the absence of adjuvant. The AHR induced to methacholine in IL-1
/ mice was significantly reduced compared with that of wild-type mice (Fig. 5). Such responses in IL-1ß/ mice were also reduced in a similar fashion to IL-1
/ mice (Fig. 5). These results suggest that both IL-1
and IL-1ß are required for AHR development.
We next examined primary OVA-specific T cell responses, and found that the levels of proliferation of DO11.10 Tg T cells cultured with the antigen-presenting cells (APC) derived from IL-1
/ and IL-1ß/ mice were partially, but not completely, decreased in the presence of OVA peptide in comparison to the wild-type levels (Fig. 6). The levels of OVA-specific IgE, but not IgG1, present in the sera of IL-1
/ mice were significantly reduced compared with wild-type sera (Fig. 7). The production of both IgG1 and IgE in response to OVA in IL-1ß/ mice, however, was lower than that of wild-type mice. Similar observations were noted for the total Ig levels in the sera of non-immunized mice (Fig. 8). These results suggest that IL-1
and IL-1ß have mutually complementary activities in T cell activation, but have differing effects on antibody production.
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Discussion
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In this study, we demonstrate that AHR is markedly reduced in IL-1
/ß/ mice, but exacerbated in IL-1Ra/ mice, and that both IL-1
and IL-1ß are required for this reaction. It was reported that the recruitment of eosinophils into the lungs was markedly reduced in IL-1RI/ mice on a 129 x B6 F1 background following OVA/alum sensitization (14). The magnitude of AHR and the number of lung-infiltrating eosinophils, however, were normal in IL-1
/ß/ mice on the BALB/cA background using a similar experimental protocol (Fig. 1 and data not shown). Then, in this study, we examined AHR in IL-1
/ß/ mice on a BALB/cA background using repeated OVA/PBS sensitization without alum. As alum induces excess Th2 responses even in the absence of IL-4R
signaling (27), the presence of alum may account for the differences obtained through the use of either OVA/alum or OVA/PBS. Since many asthmatic patients develop dramatic pathophysiological responses to low-dose allergen challenge (28), AHR induced by a weak inducer OVA/PBS, not OVA/alum, appears to reflect the general pathological predisposition of an individual. This notion is supported by the observation that both B cell-deficient and mast cell-deficient mice exhibit normal AHR development when sensitized with OVA/alum (29,30). This directly conflicts with the generally accepted notion that the activation of mast cells via antigenIgE complexes is crucial for the development of AHR (31). In contrast, AHR in mast cell-deficient mice sensitized to OVA without alum was markedly reduced (24).
IL-1 functions as both a T cell activator and a pro-inflammatory cytokine. IL-1IL-1RI signaling is responsible for the induction of VCAM-1 expression, recruiting eosinophils to the lungs during AHR (14). On the other hand, we showed that antigen-specific T cell proliferative responses, IL-4 and IL-5 production by T cells, and antigen-specific IgG1 and IgE secretion by B cells were reduced in IL-1
/ß/ mice during AHR, whereas these responses increased in IL-1Ra/ mice compared with wild-type mice. These results suggest that IL-1 plays an important role in activating Th2 cells. Consistently with these observations, involvement of IL-1 in Th2 activation, that is either dependent or independent of IL-4 and requires Lck activation, has been suggested (15,17,18). Furthermore, IL-1 induces OX40 (CD134) expression on CD4+ T cells (26), that plays an important role in Th2 cell activation (32). Interestingly, AHR in OX40/ mice is markedly reduced (33). Thus, it is suggested that IL-1 functions in AHR through activating Th2 cells.
IL-1 also potentiates Th1 cell-mediated immune responses. APC-produced IL-1 induces CD40 ligand (L) (CD154) on CD4+ T cells (26); cross-linking of CD40 on APC with CD40L leads to APC production of IL-12, IL-1
/ß and TNF-
(34). These cytokines, including IL-1, all enhance the IL-12-dependent production of IFN-
in BALB/c background mice (35). IL-4 production in IL-1RI/ mice infected with Leishmania major increased from that seen in wild-type mice, suggesting IL-1 negatively regulates IL-4 expression (36). We found that the development of delayed-type hypersensitivity reaction, mediated by Th1 cells, is significantly suppressed in IL-1
/ß/ mice on both the BALB/cA and C57BL/6J backgrounds, and that IL-1 is required for antigen-specific Th1 cell activation (Nambu et al., in preparation). Thus, IL-1 is likely involved in both Th1 and Th2 cell activation through the induction of the co-stimulatory molecules, CD40L and OX40, on CD4+ T cells.
We previously demonstrated that IL-1ß rather than IL-1
is required for T cell-dependent IgG production (20). Consistent with this observation, IgG1 production against OVA during AHR was reduced in IL-1ß/, but not IL-1
/, mice. The total and OVA-specific IgE levels in both IL-1
/ and IL-1ß/ mice, however, were reduced from the levels seen in wild-type mice. Follicular dendritic cells (FDC), which are critical in B cell Ig class switching within germinal centers, express IL-1ß, but not IL-1
(37). This evidence supports the idea that IgG1 and IgE production is reduced in IL-1ß/ mice, despite a molecular mechanism favoring the reduction of IgE levels in IL-1
/ mice. Lymphotoxin (LT)
/ mice exhibit a lack of LN and Peyers patch development, abnormal architecture of the spleen, and germinal center formation failure resulting from defects in the FDC network (38). In these mutant mice, Ig class switching in response to particle antigens, including sheep red blood cells, does not occur (38). When treated with repeated immunization with soluble protein antigen with adjuvant, Ig class switching to these antigens occurred normally in LT
/ mice despite the absence of germinal centers in the spleen (39). Thus, Ig class switching can occur independent of the FDC network and germinal center formation under specific conditions in which excess cytokines are produced. FDC produce IL-1ß, but not IL-1
(37), while Th2 cells express IL-1
(17). Although evidence may be lacking, we speculate that IL-1
, derived from Th2 cells, may have a distinct role in the regulation of IgE production functioning independently from the IL-1ß derived from germinal center FDC.
In summary, we demonstrated that both IL-1
and IL-1ß have critical roles in the development of AHR through the activation of Th2 cells during the sensitization phase. These findings may be useful to develop novel therapeutics to treat asthma.
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Acknowledgements
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We thank all the members of the laboratory for their excellent animal care. This study was supported by grants from the Ministry of Education, Science, Sport and Culture of Japan, and the Ministry of Health and Welfare of Japan.
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Abbreviations
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AChacetylcholine
APCantigen-presenting cell
AHRairway hypersensitivity response
CD40LCD40 ligand
DTHRdelayed-type hypersensitivity response
FDCfollicular dendritic cell
LNlymph node
LTlymphotoxin
IL-1RaIL-1 receptor antagonist
IL-1RI and IL-1RIIIL-1 receptor type I and type II
OVAovalbumin
TNFtumor necrosis factor
VCAMvascular cell adhesion molecule
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