Skip Navigation


International Immunology Advance Access originally published online on March 28, 2006
International Immunology 2006 18(5):701-712; doi:10.1093/intimm/dxl007
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/5/701    most recent
dxl007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Nambu, A.
Right arrow Articles by Iwakura, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nambu, A.
Right arrow Articles by Iwakura, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

IL-1ß, but not IL-1{alpha}, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses

Aya Nambu, Susumu Nakae1 and Yoichiro Iwakura

Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
1 Present address: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5176, USA

Correspondence to: Y. Iwakura; E-mail: iwakura{at}ims.u-tokyo.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
As IL-1 expression is augmented in delayed-type hypersensitivity (DTH) responses, we analyzed the role of IL-1 in this response. DTH responses against methyl BSA (mBSA) were significantly suppressed in IL-1ß-deficient (IL-1ß–/–) and IL-1{alpha}/ß–/– mice, but not in IL-1{alpha}–/– mice. In contrast, responses in IL-1R antagonist–/– (IL-1Ra–/–) mice were exacerbated. Lymph node cells derived from mBSA-sensitized IL-1ß–/–, IL-1{alpha}/ß–/– and IL-1R type I (IL-1RI)–/– mice, but not from IL-1{alpha}–/– mice, exhibited reduced proliferative responses against mBSA, while these from IL-1Ra–/– mice demonstrated augmented responses. DTH responses in wild-type mice following adoptive transfer of CD4+ T cells from mBSA-sensitized IL-1{alpha}/ß–/– mice were also reduced, while those in mice given cells derived from IL-Ra–/– mice were increased. DTH responses in IL-1RI–/–, but not IL-1{alpha}/ß–/–, mice were reduced upon transplantation of mBSA-sensitized CD4+ T cells from wild-type mice. The recall response of mBSA-sensitized CD4+ T cells against mBSA decreased upon co-culture with dendritic cells (DCs) from IL-1RI–/– mice, while the responses were normal with DCs from IL-1{alpha}/ß–/– mice. DTH responses in tumor necrosis factor {alpha}–/– (TNF–/–) mice were also suppressed; the magnitude of the suppression in IL-1{alpha}/ß–/–TNF–/– mice, however, was similar to that observed in IL-1{alpha}/ß–/– mice. These observations indicate that IL-1 possesses dual functions during the DTH response. IL-1ß is necessary for the efficient priming of T cells. In addition, CD4+ T cell-derived IL-1 plays an important role in the activation of DCs during the elicitation phase, resulting in the production of TNF, that activate allergen-specific T cells.

Keywords: allergy, cytokines, inflammation, knockout mice


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Delayed-type hypersensitivity (DTH), classified as type IV hypersensitiveness by Coombs and Gell, is an immune response mediated by a variety of inflammatory cells, including neutrophils, macrophages and T cells (1, 2). DTH develops in two phases, a sensitization phase, in which T cells are sensitized and memory T cells are formed, and an elicitation phase, in which T cell recall responses are induced upon secondary challenge with antigens. This second phase results in the induction of inflammation, involving recruitment of inflammatory cells such as neutrophils and macrophages.

Although DTH reactions are classically subdivided into tuberculin-type, Jones–Mote-type and contact hypersensitivity (CHS) reactions, in this study, we analyzed the mechanisms of tuberculin-type reaction as typical of DTH reactions. The DTH response is evoked by Th1 CD4+ T cells, whereas CD8+ T cells behave as apparent regulatory cells in this response (3). During the elicitation phase of DTH responses, neutrophils and macrophages infiltrate early into inflammatory sites, followed by T cells. IFN-{gamma}, produced by antigen-specific CD4+ T cells, plays an important role in the development of DTH responses by enhancing Th1 cell development (4), leukocyte recruitment through the induction of chemokines, such as IFN-{gamma}-inducible protein-10 (IP-10) (5), and expression of adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and P-selectin by acting on leukocytes, endothelial cells and keratinocytes (6–9). IFN-{gamma} also activates macrophages, resulting in the production of IL-1 and tumor necrosis factor {alpha} (TNF{alpha}), factors that perpetuate the local inflammation (10).

IL-1 is a pro-inflammatory cytokine that regulates multiple aspects of immune and inflammatory responses (11). The IL-1 family of cytokines includes IL-1{alpha} and IL-1ß. While these molecules both bind to two cellular receptors, IL-1R type I and type II (IL-1RI and IL-1RII, respectively) (12), the roles for these cytokines differ between types of host defense responses (13). IL-1RI, but not IL-1RII, mediates the functional activities of IL-1{alpha} and IL-1ß (12). Thus, IL-1RII is considered to be a decoy receptor that negatively regulates IL-1 activity (12). IL-1R antagonist (IL-1Ra), also a negative regulator of IL-1 function, can bind to IL-1RI without generating any signal, competing for IL-1 binding and negatively regulating IL-1{alpha} and IL-1ß signaling (12).

IL-1 contributes to the development of DTH responses by promoting the maturation of antigen-specific T cells (14) and by augmenting IL-12-dependent IFN-{gamma} production by Th1 cells (15). The development of DTH responses were reduced in mice lacking the expression of IL-1RI (IL-1RI–/– mice) (16) or treated with peptides derived from IL-1Ra (17). It has also been reported, however, that IL-1ß–/– mice exhibit normal DTH responses (18), suggesting that IL-1{alpha}, but not IL-1ß, contributes to the generation of type IV hypersensitivity reactions.

Recently, we have demonstrated that IL-1{alpha}, not IL-1ß, potently activates T cells during the sensitization phase of CHS responses (19). The role of IL-1 in DTH responses, however, remains unclear; it is unknown whether IL-1 acts as a T cell-activating factor during the sensitization phase or as a pro-inflammatory cytokine recruiting inflammatory cells during the elicitation phase.

In this study, we have analyzed the activities of IL-1 and the functional differences between IL-1{alpha} and IL-1ß in the development of DTH responses against methyl BSA (mBSA). We demonstrate that IL-1ß, but not IL-1{alpha}, functions in the development of DTH responses using IL-1{alpha}-, IL-1ß-, IL-1{alpha}/ß-, IL-1RI- and IL-1Ra-deficient mice. We also demonstrate that, in addition to the involvement of IL-1 in T cell sensitization, activated memory T cell-derived IL-1 also induces dendritic cell (DC)-mediated production of TNF, resulting in local inflammation upon secondary stimulation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Mice
IL-1{alpha}–/–, IL-1ß–/–, IL-1{alpha}/ß–/– and IL-1Ra–/– mice were generated as described (20). Animals were backcrossed to either C57BL/6J or BALB/cA mice for eight generations. IL-1RI–/– mice, kindly provided by Immunex (21), were backcrossed to C57BL/6J mice for six generations. TNF–/– mice were backcrossed for 10 generations to C57BL/6J mice (22). IL-1{alpha}/ß–/– TNF–/– mice and IL-1Ra–/–TNF–/– mice were obtained by intercrossing IL-1{alpha}/ß–/– and TNF–/– mice and IL-1Ra–/– and TNF–/– mice, respectively. C57BL/6J and BALB/cA mice were purchased from CLEA-Japan (Shizuoka, Japan). Sex- and age-matched mice, used in all experiments, received simultaneous treatment. All mice were housed under specific pathogen-free conditions in an environmentally controlled clean room (24 ± 2°C, 40–60% moisture, 8:00–20:00 lighting cycle) at the Center for Experimental Medicine, Institute of Medical Science, University of Tokyo. Animals were periodically monitored for infection. Experiments were conducted according to the institutional ethical guidelines for animal experimentation and the safety guidelines for gene manipulation experiments.

DTH response
Evaluation of DTH responses to mBSA (Sigma, St Louis, MO, USA) was performed as described (23–25). Briefly, mice were immunized subcutaneously (s.c.) with 200 µl of 1.25 mg ml–1 mBSA emulsified with CFA (Difco, Detoit, MI, USA). Seven days after immunization, mice were challenged s.c. in one footpad with 20 µl of 10 mg ml–1 mBSA in PBS. Animals were injected with an equal volume of PBS into another footpad as a control. At the indicated times after the challenge, footpad thickness was measured with a dial caliper (Mitutoyo, Tokyo, Japan). The magnitude of the DTH response was determined as follows: [footpad swelling (mm)] = [footpad thickness of mBSA-injected footpad (mm)] – [footpad thickness of PBS-injected footpad (mm)], [footpad swelling (%)] = ([footpad swelling (mm)]/[footpad thickness of PBS-injected footpad (mm)]) x 100. Footpad swelling (%) was calculated as a percentage of the mean value of the wild-type group.

Histological examination
Twenty-four hours after challenge with either mBSA or PBS, paws were removed and decalcified for 3 days by a standard protocol. After fixation with 10% PFA in PBS, specimens were embedded in paraffin. Paraffin sections were stained with hematoxylin–eosin. Structural changes and the presence of cellular infiltration in sections were determined by light microscopy.

Proliferative responses of lymph node cells
Mice were immunized with 250 µg (when IL-1–/– or IL-1RI–/– mice were immunized) or 100 µg (when IL-1Ra–/– mice were immunized) mBSA/CFA at the base of the tail and two footpads. Seven days after immunization, inguinal and popliteal lymph nodes (LN) were harvested. After preparation of a single cell suspension, LN cells were suspended in RPMI1640 (Sigma) supplemented with 10% FCS (Sigma), 50 U ml–1 penicillin (Meiji), 50 µg ml–1 streptomycin (Meiji) and 50 mM 2-mercaptoethanol (GIBCO). LN cells (5 x 105) were cultured in the presence or absence of mBSA (50 µg ml–1) in 96-well plates for 72 h, followed by the incorporation of [3H]thymidine ([3H]TdR) (0.25 mCi ml–1) (Amersham, Buckinghamshire, UK) for 9 h. Cells were then harvested using a Micro 96 well harvester (Molecular Devices, Sunnyvale, CA, USA); radioactivity was measured using a Micro Beta counter (Amersham).

Measurement of IFN-{gamma} production
IFN-{gamma} levels in LN cell culture supernatants were determined by sandwich ELISA. IFN-{gamma} Opt EIA kit (BD Biosciences Pharmingen, San Diego, CA, USA) was used for the detection of IFN-{gamma}. Resulting absolute cytokine levels were determined according to the manufacturer's protocol. The detection limit of the assay for IFN-{gamma} was >5 pg ml–1.

Measurement of serum anti-mBSA IgG
Sera were collected prior to immunization with mBSA/CFA and 4 days after the second immunization with DTH. Anti-mBSA IgG levels were measured by ELISA (25). Briefly, 96-well plates were coated overnight with 100 µl of a 5 µg ml–1 mBSA solution at 4°C, then blocked by incubation with 0.1% skim milk (CO-OP, Tokyo, Japan) in PBS for 1 h at room temperature (r.t.). After washing three times in PBS + 0.05% Tween 20, 100 µl of each mouse serum, diluted 316-fold in PBS, was added for 1 h at r.t. After another round of extensive washing, we added 100 µl of alkaline phosphatase (AP)-conjugated goat anti-mouse IgG (ZYMED, San Francisco, CA, USA). After a 1-h incubation at r.t., plates were washed three times. AP activities were measured on a microplate-reader MP-120 (CORONA, Ibaragi, Japan) using p-nitrophenylphosphate SIGMA104® (Sigma) as the substrate.

Adoptive transfer of sensitized T cells
For adoptive T cell transfer experiments, LN cell suspensions were prepared from mBSA/CFA-sensitized mice as described above. To purify CD4+ T cells, LN cells were incubated with anti-mouse B220, CD8, Ter-119 and NK-1.1 microbeads (Miltenyi Biotech, Auburn, CA, USA). CD4+ T cells were isolated following negative selection on a MACS column. We injected the purified CD4+ T cells (2 x 107 cells per mouse) into the tail vain of recipient mice. After 19 h, mice were challenged with mBSA or PBS only into the left or right footpad, respectively. Swelling was monitored over the following days.

mBSA-specific CD4+ T cell proliferation
CD4+ T cells were purified (>90% CD4+ cells) from the draining LNs of immunized mice by positive selection using anti-CD4 magnetic beads (MACS; Miltenyi Biotech). CD11c+ cells (DCs) were purified (>90% CD11c+ cells) from non-immunized splenocytes using anti-CD11c magnetic beads (MACS; Miltenyi Biotech). CD4+ T cells (1 x 105) were cultured for 72 h with 1 x 104 DCs in the presence or absence of 50 µg ml–1 mBSA in RPMI1640 (Sigma) complete medium. Proliferation was assessed by measurement of [3H]TdR (0.25 mCi ml–1) (Amersham) incorporation.

Reverse transcription–PCR
Total RNA from CD4+ T cells was isolated by the acid guanidinium thiocyanate-phenol-chloroform extraction (AGPC) method. For reverse transcription (RT), 5 µg of total RNA was transcribed using SuperScript III transcriptase according to the manufacturer's protocol of SuperScript first-strand synthesis system for RT–PCR (Invitrogen, San Diego, CA, USA). The PCR mixture contained 1x PCR buffer, 1.5 mM MgCl2, 0.2 mM deoxynucleoside triphosphate mix, a 5' and 3' primer (each at 0.2 µM), 2 units Ex Taq DNA polymerase (TaKaRa Bio Inc., Shiga, Japan) and 5 µl (10% of total volume) of the products of RNA reverse transcription in a total volume of 50 µl. After an initial denaturation at 94°C for 2 min, 30 cycles of denaturation (94°C for 20 s), annealing (55°C for 30 s) and extension (72°C for 45 s) were performed using a DNA thermal cycler (icycler, Bio-Rad, Hercules, CA, USA). The primers for PCR amplifying IL-1{alpha}, IL-1ß, IL-1RI, IL-1Ra and hypoxanthine phosphoribosyltransferase (HPRT) are as follows: forward, 5'-GAGATACAAACTGATGAAGCTC-3', and reverse, 5'-CAGAAGAAAATGAGGTCGGTC-3' (IL-1{alpha}); forward, 5'-CCTGAACTCAACTGTGAAATGCC-3', and reverse, 5'-TCATCATCATCCCATGAGTCAC-3' (IL-1ß); forward, 5'-CTGTAAACCTCTGCTTCTTGAC-3', and reverse, 5'-ACAACACAGATAAACGGATAGCG-3' (IL-1RI); forward, 5'-GACCCTGCAAGATGCAAGCC-3', and reverse, 5'-GAGCGGATGAAGGTAAAGCG-3' (IL-1Ra); forward, 5'-GTTGGATACAGGCCAGACT-3', and reverse, 5'-CAGGGTAGGCTGGCCTATAGGCT-3' (HPRT).

Statistical analysis
Each experiment was repeated at least three times. Statistical analysis was performed using the Student's t-test. A mean ± SD is shown for all figures. P-values <0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
DTH response in IL-1 KO mice
To elucidate the role of IL-1 in DTH responses, we examined mBSA-induced hypersensitivity in IL-1–/– mice. Footpad swelling in IL-1{alpha}/ß–/– mice on the C57BL/6J background was significantly reduced compared with that seen in wild-type mice (Fig. 1A). A similar reduction was also observed in IL-1RI–/– mice, consistent with the results of Labow et al. (16). In contrast, footpad swelling in IL-1Ra–/– mice was markedly enhanced (Fig. 1B). Similar observations were obtained in IL-1{alpha}/ß–/– mice on the BALB/cA background (data not shown).


Figure 1
View larger version (13K):
[in this window]
[in a new window]
  		Fig. 1. Induction of DTH responses in IL-1{alpha}/ß–/–, IL-1RI–/– and IL-1Ra–/– mice. Mice were sensitized s.c. with mBSA/CFA (250 µg in A, 100 µg in B). One week after sensitization, PBS or mBSA was injected into the footpads of each mouse. Footpad thickness was measured 24 h after the second challenge. Circles indicate the levels for individual mice; a bar shows the mean ± SD for each group. The numbers of the mice used were (A) wild type, n = 12; IL-1{alpha}/ß–/–, n = 7 and IL-1RI–/–, n = 5; (B) wild type, n = 8, and IL-1Ra–/–, n = 4. **P < 0.01 versus wild-type mice.

 
In the mBSA-injected footpads of wild-type mice, we observed the infiltration of inflammatory cells mainly consisting of neutrophils and lymphocytes in the dermis surrounding small vessels; these infiltrates were not observed in PBS-injected footpads (Fig. 2A–D). Consistent with the reduced footpad thickness (Fig. 1), the numbers of infiltrating cells in the mBSA-challenged footpads of IL-1RI–/– and IL-1{alpha}/ß–/– mice (Fig. 2F and G) were significantly lower than those in wild-type mice, although these levels were increased in comparison with those seen in PBS-injected footpads (Fig. 2B and C). In contrast, a greater number of inflammatory cells were observed in the mBSA-injected footpads of IL-1Ra–/– mice than that seen in wild-type mice (Fig. 2H). The cellular composition infiltrated into the inflammatory sites was similar (data not shown) among IL-1{alpha}/ß–/–, IL-1RI–/– and IL-1Ra–/– mice (Fig. 2I–L). These results indicate that IL-1 plays an important role in the development of mBSA-induced DTH responses.


Figure 2
View larger version (103K):
[in this window]
[in a new window]
  		Fig. 2. Histology of footpads from DTH-induced mice. Sections of footpads challenged with PBS (A, B, C and D) or mBSA (E–H) were stained with hematoxylin and eosin. (A) and (E), wild-type mice; (B) and (F), IL-1{alpha}/ß–/– mice; (C) and (G), IL-1RI–/– mice (D) and (H), IL-1Ra–/– mice. "v" points to small vessels. Filled arrow heads in (E–H) indicate infiltration of inflammatory cells in the dermis surrounding small vessels. (A–H): x400 and (I–L): x1000

 
The role for IL-1 in the activation of mBSA-specific T cells
As IL-1 functions as a T cell co-stimulatory molecule in the antigen-specific T cell activation observed during the sensitization phase of immune responses (19, 26), we examined the effect of IL-1 deficiency on antigen-specific T cell responses following mBSA sensitization. Seven days after mBSA sensitization, isolated inguinal LN cells were cultured in the presence or absence of mBSA. LN T cell proliferative responses against mBSA were reduced in both IL-1RI–/– and IL-1{alpha}/ß–/– mice from the levels seen in wild-type mice (Fig. 3A). Under these conditions, IFN-{gamma} levels in the supernatants of LN cell cultures derived from IL-1RI–/– and IL-1{alpha}/ß–/– mice were decreased in comparison with those observed in LN cell cultures from wild-type mice (Fig. 3B). The levels of IL-4 in these LN cell cultures, however, were below the assay limit of the detection among these LN cell cultures (data not shown). The mBSA-specific proliferative responses of LN cells from IL-1Ra–/– mice were increased 2.2-fold from those seen in cultures from wild-type mice (Fig. 3C); the IFN-{gamma} levels in supernatants from IL-1Ra–/– LN cell cultures were also elevated (Fig. 3D). These results indicate that IL-1 is required for optimal T cell activation during the sensitization phase of DTH responses induced by mBSA.


Figure 3
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 3. Proliferative responses and IFN-{gamma} production of LN cells after stimulation with mBSA. Mice were immunized with mBSA/CFA (250 µg in A, B, D; 100 µg in C) as described in Methods. (A), (C) Seven days after immunization, LN cells were harvested. After stimulation with mBSA for 72 h, proliferative responses were measured by [3H]TdR incorporation. A mean ± SD of triplicate measurements is shown. (B), (D) IFN-{gamma} levels in the pooled culture supernatants of triplicate wells from proliferative response assay were determined by ELISA. Similar results were obtained at least in three independent experiments. **P < 0.01 versus wild-type mice.

 
Differential roles of IL-1{alpha} and IL-1ß in DTH response
To clarify the differential roles of IL-1{alpha} and IL-1ß in the development of DTH responses, we have examined the expression of IL-1{alpha} and IL-1ß during DTH reaction. Mice were immunized with mBSA/CFA, and after 3 days (for the sensitization phase) or 7 days (for the elicitation phase), the LN cells were harvested. Then, the mRNA levels for IL-1{alpha} and IL-1ß were determined by real-time PCR. We found that the IL-1ß expression level in the LN cells was much higher than that of IL-1{alpha} both at the sensitization and elicitation phases (the content of IL-1ß mRNA in total IL-1 mRNA: 90% at 3 days after sensitization and 65% at 7 days). The expression level of IL-1ß in the inflamed footpads at the elicitation phase was also much higher than that of IL-1{alpha} (80% IL-1ß). Thus, IL-1ß is mainly produced during DTH responses.

Then, we examined mBSA-induced hypersensitivity in IL-1{alpha}–/– and IL-1ß–/– mice on the C57BL/6J background. Footpad swelling differed markedly among IL-1{alpha}–/–, IL-1ß–/– and wild-type mice; swelling was significantly suppressed in IL-1ß–/– and IL-1{alpha}/ß–/– mice, while it was unaffected in IL-1{alpha}–/– mice (Fig. 4A). Microscopic analyses coincided well with these observations (data not shown). Similar results were also observed in mice on the BALB/cA background (data not shown).


Figure 4
View larger version (20K):
[in this window]
[in a new window]
  		Fig. 4. DTH responses in IL-1{alpha}–/– and IL-1ß–/– mice. mBSA-induced DTH responses in IL-1{alpha}–/– and IL-1ß–/– mice were examined as in Fig. 1. (A) Circles indicate the severity of DTH of individual mice. The mean ± SD of each group is shown. Wild type, n = 11; IL-1{alpha}–/–, n = 9; IL-1ß–/–, n = 9 and IL-1{alpha}ß–/–, n = 8. **P < 0.01 versus wild-type mice. (B) mBSA-specific LN cell proliferation was assessed by [3H]TdR incorporation. A mean ± SD of triplicate measurements is shown. *P < 0.05 versus wild-type mice. (C) IFN-{gamma} levels in pooled culture supernatants of the triplicate wells from the proliferative response assay were determined by ELISA. These results were reproducible in three independent experiments. (D) mBSA-specific IgG levels in sera from DTH-induced mice were determined by ELISA. Circles indicate the levels observed in individual mice. The mean ± SD of each group is also shown. Wild type, n = 18; IL-1{alpha}–/–, n = 11 and IL-1ß–/–, n = 10. *P < 0.05 versus wild-type mice.

 
The mBSA-specific proliferative responses of LN cells after sensitization with mBSA were significantly reduced in both IL-1ß–/– and IL-1{alpha}/ß–/– mice in comparison with IL-1{alpha}–/– and wild-type mice (Fig. 4B). No significant differences were observed between wild-type mice and IL-1{alpha}–/– mice. Interestingly, upon stimulation with mBSA, IFN-{gamma} levels in the supernatants of LN cell cultures prepared from both IL-1{alpha}–/– and IL-1ß–/– mice were decreased from the levels observed in wild-type mice (Fig. 4C). After antigen stimulation, IFN-{gamma} production in IL-1{alpha}/ß–/– LN cell cultures was significantly reduced in comparison with IL-1ß–/– cell cultures. Although IL-1{alpha} did not enhance the proliferative responses of LN cells, these findings suggest that both IL-1{alpha} and IL-1ß are involved in the production of IFN-{gamma}.

We next examined mBSA-specific antibody production in IL-1-deficient mice. At 4 days after the second challenge with mBSA, mBSA-specific IgG levels in sera were determined by ELISA during the DTH response. mBSA-specific IgG levels were reduced both in IL-1{alpha}–/– and IL-1ß–/– mice in comparison with those observed in wild-type mice (Fig. 4D). The DTH response was only suppressed in IL-1ß–/– mice. Thus, both IL-1{alpha} and IL-1ß are involved in mBSA-specific antibody production. These results suggested, however, that these antibodies may not be involved in DTH responses.

An important role for IL-1 in mBSA-specific T cell sensitization in vivo
To discriminate the roles of IL-1 in the sensitization of T cells from its function in the elicitation of inflammation, we performed the adoptive transfer of mBSA-sensitized T cells. Mice were first immunized with mBSA/CFA. One week after immunization, we purified T cells from the draining LNs of these mice. These cells were injected intravenously into naive wild-type mice. Measurement of the development of DTH revealed that footpad swelling was significantly suppressed in mice that received mBSA-sensitized IL-1{alpha}/ß–/– T cells in comparison with animals that were given wild-type T cells (Fig. 5A). In contrast, footpad swelling in mice that received mBSA-sensitized IL-1Ra–/– T cells was significantly increased (Fig. 5B). These results indicate that IL-1 is required for antigen-specific T cell priming during the sensitization phase of mBSA-induced DTH responses.


Figure 5
View larger version (25K):
[in this window]
[in a new window]
  		Fig. 5. Analysis of the role of IL-1 in the sensitization and elicitation phases of DTH responses. LN cells (2 x 107 cells per mouse) from mice immunized with mBSA/CFA were transferred into non-sensitized mice intravenously. Nineteen hours after injection, recipient mice were challenged with PBS or mBSA in footpads. Footpad swelling was measured as in Fig. 1. (A) Wild-type mice received wild-type T cells (n = 5) or IL-1{alpha}/ß–/– T cells (n = 6), (B) wild-type mice received wild-type T cells (n = 9) or IL-1Ra–/– T cells (n = 12), (C) wild-type mice received wild-type T cells (n = 23), IL-1{alpha}/ß–/– mice received wild-type T cells (n = 14) or IL-1RI–/– mice received wild-type T cells (n = 13), (D) wild-type mice received wild-type T cells (n = 10) or IL-1Ra–/– mice received wild-type T cells (n = 10). Circles indicate the levels for individual mice. The mean ± SD of each group is also shown. *P < 0.05 versus wild-type mice. (E) Mice were immunized with mBSA or left untreated. After 7 days, CD4+ T cells were purified and cultured for 0, 24 or 48 h. IL-1{alpha}, IL-1ß, IL-1RI and IL-1Ra mRNA expression were examined by RT–PCR. "–," non-immunized mice; N, without RT. HPRT mRNA levels served as an internal control.

 
The role for IL-1 in the elicitation of DTH response
To elucidate the role of IL-1 in the elicitation phase of DTH responses, we adoptively transferred mBSA-sensitized wild-type T cells into wild-type, IL-1{alpha}/ß–/–, IL-1RI–/– and IL-1Ra–/– mice. We observed a similar footpad swelling in wild-type and IL-1{alpha}/ß–/– mice, while the resulting footpad swelling in IL-1RI–/– mice was markedly decreased (Fig. 5C). Footpad swelling in IL-1Ra–/– mice receiving mBSA-sensitized T cells was significantly increased in comparison to that seen in wild-type recipient mice (Fig. 5D). These results suggest that donor T cell-produced IL-1 activates recipient leukocytes to induce inflammation. In support for this notion, both IL-1{alpha} and IL-1ß were transiently expressed in sensitized CD4+ T cells after a 24-h co-culture with mBSA (Fig. 5E). These observations indicate that IL-1, primarily that derived from T cells, is responsible for the induction of local inflammation during the elicitation phase of DTH responses.

An important role for IL-1 in the activation of DCs during elicitation phase
We next analyzed the effect of T cell-derived IL-1 on the activation of antigen-presenting cells (APCs) during the elicitation phase. We isolated CD4+ T cells 7 days after the immunization of wild-type mice with mBSA. Purified cells were co-cultured with DCs from naive wild-type, IL-1{alpha}/ß–/–, IL-1RI–/– and IL-1Ra–/– mice in the presence or absence of mBSA. mBSA-specific CD4+ T cell proliferative responses were significantly reduced following co-culture with IL-1RI–/– DCs, while co-cultures with IL-1{alpha}/ß–/– DCs generated similar proliferation as that observed in wild-type DCs (Fig. 6A). T cell proliferation in the presence of IL-1Ra–/– DCs, however, was up-regulated (Fig. 6B). These results indicate that T cell-derived IL-1 is important for DC activation, a process that is critical for the subsequent proliferation of antigen-specific CD4+ T cells.


Figure 6
View larger version (20K):
[in this window]
[in a new window]
  		Fig. 6. Effects of DC-derived IL-1 on CD4+ T cell proliferation. CD4+ T cells (1 x 105 per well) from mBSA-immunized wild-type mice were co-cultured with CD11c+ DC cells from a different genotype (1 x 104 per well) in the presence or absence of mBSA. The proliferative responses of T cells were measured by [3H]TdR incorporation. (A) Wild type (WT), IL-1{alpha}/ß–/– and IL-1RI–/– DCs. (B) WT and IL-1Ra–/– DCs. [3H]TdR incorporation was measured in three wells; the mean ± SD of these values is shown. Similar results were obtained in three independent experiments. *P < 0.05 versus wild type.

 
Involvement of TNF downstream of IL-1 in the DTH response
TNF is a potent pro-inflammatory cytokine with similar biological activities to IL-1. As IL-1 deficiency only partially reduced the DTH response induced by mBSA (Fig. 1) and IL-1-deficient DCs could activate memory T cells in recall responses (Fig. 6), we examined the possible involvement of TNF in the development of type IV hypersensitivity. Footpad swelling of TNF–/– mice was significantly, if only slightly, reduced (~80%) from the levels seen in wild-type mice (Fig. 7A), suggesting the involvement of TNF in DTH responses. Footpad swelling in IL-1{alpha}/ß–/–TNF–/– mice, however, was similar to that seen in IL-1{alpha}/ß–/– mice (~60%) (Fig. 7A). No additional effect of TNF deficiency on DTH response could be observed in IL-1{alpha}/ß–/– mice. The footpad swelling of IL-1Ra–/–TNF–/– mice, however, was markedly reduced in comparison with that of IL-1Ra–/– mice (Fig. 7B). These results are compatible with the hypothesis that TNF is induced downstream of IL-1 signaling and a portion of the biological activities induced by IL-1 may occur through the induction of TNF.


Figure 7
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 7. Roles of IL-1 and TNF in DTH responses. mBSA-induced DTH responses in wild-type, IL-1{alpha}/ß–/–, TNF–/– and IL-1{alpha}/ß–/–TNF–/– mice (A) and in wild-type, IL-1Ra–/– and IL-1Ra–/–TNF–/– mice (B) were examined as in Fig. 1. Circles indicate disease severity of individual mice. The mean ± SD of each group is shown. (A) Wild type, n = 12; IL-1{alpha}/ß–/–, n = 7; TNF–/–, n = 8 and IL-1{alpha}/ß–/–TNF–/–, n = 7. **P < 0.01, *P < 0.05 versus wild-type mice and # P < 0.05 versus TNF–/– mice. (B) Wild type, n = 5; IL-1Ra–/–, n = 6 and IL-1Ra–/–TNF–/–, n = 6. *P < 0.05 versus wild-type mice and ***P < 0.05 versus IL-1Ra–/– mice.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Using IL-1{alpha}–/– and IL-1ß–/– mice, we demonstrated that IL-1ß, more so than IL-1{alpha}, plays an important role in the development of DTH responses. The proliferative recall responses of T cells derived from both IL-1{alpha}/ß–/– mice and IL-1ß–/– mice, but not those from IL-1{alpha}–/– mice, were significantly reduced, suggesting that IL-1ß functions in T cell sensitization. With regard to the function of IL-1 in the sensitization of T cells, we previously showed that IL-1 activate T cells by inducing CD40L and OX40 expression in T cells (26). Recently, it was also shown that IL-1ß signaling can activate naive T cells through activation of c-Rel (27).

The involvement of IL-1ß in T cell sensitization was also suggested by the responses observed during airway hypersensitivity responses (28, 29). In contrast, IL-1{alpha}, but not IL-1ß, is crucial for the CHS reaction (19), and both IL-1{alpha} and IL-1ß are important for the antibody production against mBSA during DTH reaction. As IL-1{alpha} and IL-1ß bind the same receptors, it seems likely that differential expression of these molecules may explain the differential roles of these molecules among different allergic reactions. In support for this idea, we showed that IL-1ß is mainly produced during DTH reactions. The reason why specific IL-1 species are produced during different allergic reactions is not resolved completely. With regard to this, it was reported that different APCs, the major producer of IL-1 during T cell sensitization (30), are required for the antigen presentation during sensitization phase; DCs play a key role in DTH reactions while Langerhans cells (LCs) play an essential role in CHS reactions (3). Human DC1 cells, derived from monocytes, synthesize IL-1{alpha} but DC2 cells, derived from plasmacytoid cells, do not (31). CD11a–CC81–MyD-1+ DCs from bovine afferent lymph synthesized IL-1{alpha} and stimulated both CD4+ and CD8+ T cells, while CD11a+CC81+MyD-1– DCs that did not synthesize IL-1{alpha} could not stimulate CD8+ T cells (32). On the other hand, both IL-1{alpha} and IL-1ß are produced in LCs (19). Thus, it is possible that CD4+ T cells that are involved in the DTH response as well as in airway hypersensitivity are stimulated by a particular sub-population of DCs that synthesizes only IL-1ß. However, the exact mechanism for the functional discrimination between IL-1{alpha} and IL-1ß remains to be elucidated.

DTH response has been reported to occur normally in IL-1ß–/– mice (18). The apparent discrepancy to our results, following two points should be noted. First, the mBSA dosage and the immunization route that they used were different from that we used in the present experiments. It is possible that other cytokines may compensate the deficiency of IL-1ß when antigenic stimulation is very strong. In support for this notion, Shornick et al. (33) demonstrated that IL-1ß deficiency could be overcome either by application of very high doses of sensitizing antigen or by local intra-dermal injection of recombinant IL-1ß before antigen application. Second, the genetic backgrounds of the mice used in the experiments were different between these two studies; we used IL-1ß–/– mice that were backcrossed to either C57BL/6J mice or BALB/cA mice for eight generations, whereas they studied in 129 x B6 IL-1ß–/– mice. It is possible that a small difference of footpad swelling could not be detected on the mixed background mice.

IFN-{gamma} is a Th1 cytokine and is critically involved in the development of DTH responses (34, 35). IFN-{gamma} production by CD4+ T cells was reduced both in IL-1{alpha}–/– and IL-1ß–/– mice after immunization with mBSA, suggesting that IL-1 induces the production of IFN-{gamma} either by activating T cells or, in the case of IL-1{alpha}, by directly stimulating IFN-{gamma} gene transcription as a transcription factor (36). This suppression of IFN-{gamma} production, however, does not explain the differential sensitivity of IL-1{alpha}–/– and IL-1ß–/– mice to the DTH responses, because the IFN-{gamma} production was similar between both mutant mice. Thus, IFN-{gamma} production by IL-1{alpha}–/– T cells is sufficient or some other factors compensate for the deficiency of this cytokine to induce a full magnitude DTH response. With this respect, it was reported that DTH reaction is suppressed in IFN-{gamma}–/– mice when mice were immunized with antigen alone (37, 38). Since DTH response and pro-inflammatory cytokine expression are much enhanced in the presence of adjuvant, our results suggest that some other cytokines may compensate for the function of IFN-{gamma}. We observed similar compensatory effects of adjuvant for the deficiency of a cytokine in airway hypersensitivity responses (26). In this connection, we examined expression of chemokines in IL-1-deficient mice. The expression levels of RANTES, IP-10 and monocyte chemoattractant protein-1 (MCP-1) were similar between IL-1{alpha}–/– and IL-1ß–/– mice in the elicitation phase. Thus, these chemokine expression levels also could not explain the difference of the DTH responses between IL-1{alpha}–/– and IL-1ß–/– mice, indicating involvement of other factors.

We also discovered that antibody production against mBSA was reduced both in IL-1{alpha}–/– and IL-1ß–/– mice, indicating that both IL-1{alpha} and IL-1ß are involved in this humoral immune response. However, T cell sensitization was reduced only in IL-1ß–/– mice. Thus, IL-1 may also function in the process of antibody production other than T cell sensitization. With regard to this, it is known that IL-1 activates DCs and induces maturation of DCs (39–42). IL-1 also stimulates the proliferation of splenic B cells after crossing of their surface Igs (43) and by signals through CD40 and IL-4R (44), and promotes the survival of germinal center B cells (45). IL-1 is strongly expressed in follicular DCs in the germinal center, which play important roles in affinity maturation and isotype switch of Igs through interaction with B cells (46). As another possibility, since IFN-{gamma} plays an important role in the class switching of IgG in B cells (47, 48), the reduction of IFN-{gamma} production in IL-1{alpha}–/– and IL-1ß–/– mice may cause reduction of antibody production against mBSA. These data also indicate that antibody levels against mBSA do not affect greatly the development of DTH, as normal DTH responses were observed in IL-1{alpha}–/– mice. The relative independence of DTH on humoral immune responses was also suggested by Lagrange et al. (49).

In addition to a role in the sensitization of T cells, IL-1 is also involved in the elicitation of local inflammation during DTH responses. The development of DTH was severely suppressed following the adoptive transfer of mBSA-immunized CD4+ T cells into IL-1RI–/– mice, but not IL-1{alpha}/ß–/– mice, suggesting that activated CD4+ T cell-derived IL-1 plays an important role in the elicitation phase. We also demonstrated that IL-1ß derived from activated memory T cells is required for the activation of DCs that activate antigen-specific T cells at inflammatory sites. It is known that IL-1 enhances T-dependent immune responses by amplifying the function of DCs (50). IL-1ß acts on APCs to enhance the in vivo proliferation of antigen-stimulated naive CD4+ T cells (40), but it does not induce the expression of CD80, CD134 ligand, 4-1BBL or glucocorticoid-induced TNF (40). IL-1ß induces functional maturation of DCs by inducing CD40, CD86 and MHC class II (39), although we could not detect any defects in IL-1-deficient DCs (30). In addition, IL-1ß induces DCs to secrete IL-12 leading to the activation of cellular immunity (42). Thus, T cell-derived IL-1ß may enhance maturation of immature DCs and activate DCs to enhance inflammation during the elicitation phase of the DTH response. These observations suggest dual functions for IL-1 in DTH reactions. During the sensitization phase, IL-1 produced by DCs activates T cells; during the elicitation phase, T cell-derived IL-1 activates DCs to enhance antigen presentation and/or cytokine production.

As IL-1 deficiency only partially reduced the DTH response, it was suggested that other factors contributed to the response. Accordingly, we examined the contribution of TNF, which plays an important role in the development of inflammation during the elicitation phase (26), and found that the elevated DTH response in IL-1Ra–/– mice was cancelled by TNF deficiency, indicating that the actions of IL-1 are mediated in part by TNF. Other hypersensitivity responses, collagen- and antigen-induced arthritis and experimental autoimmune encephalomyelitis, are also suppressed in TNF–/–, TNFRI–/– and TNFRII–/– mice, indicating the importance of this cytokine (51–56). Interestingly, however, the severity of DTH in IL-1{alpha}/ß–/–TNF–/– triple mutant mice did not differ from IL-1–/– mice (Fig. 7). With regard to this, we previously demonstrated that TNF production is induced downstream of IL-1 signaling and TNF is not induced in the absence of IL-1 (26). Thus, it seems unlikely that TNFs compensate for the deficiency of IL-1. In this context, several factors are suggested to be involved in the development of DTH responses. Exacerbated inflammation is observed when MCP-1 (57, 58), IL-12 and IL-18 (1, 59) are over-expressed, and on the contrary, DTH responses are suppressed in the absence of these molecules, suggesting that these molecules contribute to the DTH responses through IL-1-independent pathway. Recently, it was also demonstrated that IL-16, a chemoattractant for CD4+ leukocytes (60), is induced in the inflamed footpads and the treatment with anti-IL-16 can inhibit the recruitment of not only CD4+ T cells but also macrophages (24).

In summary, IL-1ß, more so than IL-1{alpha}, is critical in the development of DTH responses, functioning as both a T cell co-stimulatory molecule and a pro-inflammatory cytokine. T cell-derived IL-1 contributes to the induction of local inflammation by activating DCs. Polymorphism in the genes for both IL-1ß and IL-1Ra has been shown to influence both DTH responses against Mycobacterium tuberculosis and disease manifestations in human tuberculosis (61). Therefore, our findings may provide a rationale explaining the dependence of the disease on IL-1 gene polymorphisms, which may aid in the future development of novel therapeutics.


   Acknowledgements
 
We thank K. Sekikawa for providing the TNF–/– mice and K. Sudo, R. Horai, S. Kakuta and M. Kadoki (University of Tokyo, Tokyo, Japan) for technical support in the experiments. We also thank all the members of the laboratory for discussion and help in animal care. This work was supported by grants from the Ministry of Education, Culture, Sport and Science of Japan and the Ministry of Health and Welfare of Japan.


   Abbreviations
 
AP, alkaline phosphatase
APC, antigen-presenting cell
CHS, contact hypersensitivity
DC, dendritic cell
DTH, delayed-type hypersensitivity
HPRT, hypoxanthine phosphoribosyltransferase
IL-1Ra, IL-1R antagonist
IL-1RI, IL-1R type I
IL-1RII, IL-1R type II
LC, Langerhans cells
LN, lymph node
mBSA, methyl BSA
MCP-1, monocyte chemoattractant protein-1
RT, reverse transcription
r.t., room temperature
s.c., subcutaneously
TNF, tumor necrosis factor

   Notes
 
Transmitting editor: K. Sugamura

Received 27 May 2005, accepted 7 February 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Kobayashi K., Kaneda K. and Kasama T. 2001. Immunopathogenesis of delayed-type hypersensitivity. Microsc. Res. Tech. 53: 241.[CrossRef][Web of Science][Medline]
  2. Black C. A. 1999. Delayed type hypersensitivity: current theories with an historic perspective. Dermatol. Online J. 5: 7.[Medline]
  3. Grabbe S. and Schwarz T. 1998. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19: 37.[CrossRef][Web of Science][Medline]
  4. Kariyone A., Tamura T., Kano H. et al. 2003. Immunogenicity of peptide-25 of Ag85B in Th1 development: role of IFN-gamma. Int. Immunol. 15: 1183.[Abstract/Free Full Text]
  5. Molesworth-Kenyon S. J., Oakes J. E. and Lausch R. N. 2005. A novel role for neutrophils as a source of T cell-recruiting chemokines IP-10 and Mig during the DTH response to HSV-1 antigen. J. Leukoc. Biol. 3: 3.
  6. Bochner B. S., Luscinskas F. W., Gimbrone M. A., et al. 1991. Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J. Exp. Med. 173: 1553.[Abstract/Free Full Text]
  7. Walsh G. M., Mermod J. J., Hartnell A., Kay A. B. and Wardlaw A. J. 1991. Human eosinophil, but not neutrophil, adherence to IL-1-stimulated human umbilical vascular endothelial cells is alpha 4 beta 1 (very late antigen-4) dependent. J. Immunol. 146: 3419.[Abstract]
  8. Iademarco M. F., Barks J. L. and Dean D. C. 1995. Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells. J. Clin. Invest. 95: 264.[Web of Science][Medline]
  9. Thorlacius H., Lindbom L. and Raud J. 1997. Cytokine-induced leukocyte rolling in mouse cremaster muscle arterioles in P-selectin dependent. Am. J. Physiol. 272: H1725.[Medline]
  10. Ferreri N. R., Millet I., Paliwal V. et al. 1991. Induction of macrophage TNF alpha, IL-1, IL-6, and PGE2 production by DTH-initiating factors. Cell. Immunol. 137: 389.[CrossRef][Web of Science][Medline]
  11. Dinarello C. A. 1996. Biologic basis for interleukin-1 in disease. Blood 87: 2095.[Abstract/Free Full Text]
  12. Dinarello C. A. 1997. Interleukin-1. Cytokine Growth Factor Rev. 8: 253.[CrossRef][Medline]
  13. Song X., Voronov E., Dvorkin T. et al. 2003. Differential effects of IL-1alpha and IL-1beta on tumorigenicity patterns and invasiveness. J. Immunol. 171: 6448.[Abstract/Free Full Text]
  14. Igarashi K., Mitsuyama M., Muramori K., Tsukada H. and Nomoto K. 1990. Interleukin-1-induced promotion of T-cell differentiation in mice immunized with killed Listeria monocytogenes. Infect. Immun. 58: 3973.[Abstract/Free Full Text]
  15. Shibuya K., Robinson D., Zonin F. et al. 1998. IL-1 alpha and TNF-alpha are required for IL-12-induced development of Th1 cells producing high levels of IFN-gamma in BALB/c but not C57BL/6 mice. J. Immunol. 160: 1708.[Abstract/Free Full Text]
  16. Labow M., Shuster D., Zetterstrom M. et al. 1997. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J. Immunol. 159: 2452.[Abstract/Free Full Text]
  17. Kluczyk A., Siemion I. Z., Slon-Usakiewicz J. J. and Wieczorek Z. 1997. Immunomodulatory activity of oligopeptides related to interleukin 1 receptor antagonist sequence. Arch. Immunol. Ther. Exp. (Warsz) 45: 427.[Medline]
  18. Zheng H., Fletcher D., Kozak W. et al. 1995. Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice. Immunity 3: 9.[CrossRef][Web of Science][Medline]
  19. Nakae S., Naruse-Nakajima C., Sudo K., Horai R., Asano M. and Iwakura Y. 2001. IL-1alpha, but not IL-1beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity. Int. Immunity. 13: 1471.
  20. Horai R., Asano M., Sudo K. et al. 1998. Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1 alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187: 1463.[Abstract/Free Full Text]
  21. Glaccum M. B., Stocking K. L., Charrier K. et al. 1997. Phenotypic and functional characterization of mice that lack the type I receptor for IL-1. J. Immunol. 159: 3364.[Abstract]
  22. Taniguchi T., Takata M., Ikeda A., Momotani E. and Sekikawa K. 1997. Failure of germinal center formation and impairment of response to endotoxin in tumor necrosis factor alpha-deficient mice. Lab. Investig. 77: 647.[Web of Science][Medline]
  23. Sarnstrand B., Jansson A. H., Matuseviciene G., Scheynius A., Pierrou S. and Bergstrand H. 1999. N,N'-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents. J. Pharmacol. Exp. Ther. 288: 1174.[Abstract/Free Full Text]
  24. Yoshimoto T., Wang C. R., Yoneto T., Matsuzawa A., Cruikshank W. W. and Nariuchi H. 2000. Role of IL-16 in delayed-type hypersensitivity reaction. Blood 95: 2869.[Abstract/Free Full Text]
  25. Ohshima S., Saeki Y., Mima T. et al. 1998. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl Acad. Sci. USA 95: 8222.[Abstract/Free Full Text]
  26. Nakae S., Komiyama Y., Narumi S. et al. 2003. IL-1-induced tumor necrosis factor-alpha elicits inflammatory cell infiltration in the skin by inducing IFN-gamma-inducible protein 10 in the elicitation phase of the contact hypersensitivity response. Int. Immunol. 15: 251.[Abstract/Free Full Text]
  27. Banerjee D., Liou H. C. and Sen R. 2005. c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity 23: 445.[CrossRef][Web of Science][Medline]
  28. Nakae S., Komiyama Y., Yokoyama H. et al. 2003. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int. Immunol. 15: 483.[Abstract/Free Full Text]
  29. Nakae S., Horai R., Asano M. and Iwakura I. 2001. Interleukin-1beta, but not Interleukin-1alpha, is required for T-cell-dependent antibody production. Immunology 104: 402.[CrossRef][Web of Science][Medline]
  30. Nakae S., Asano M., Horai R., Sakaguchi N. and Iwakura Y. 2001. IL-1 enhances T cell-dependent antibody production through induction of CD40 ligand and OX40 on T cells. J. Immunol. 167: 90.[Abstract/Free Full Text]
  31. Rissoan M. C., Soumelis V., Kadowaki N. et al. 1999. Reciprocal control of T helper cell and dendritic cell differentiation. Science 283: 1183.[Abstract/Free Full Text]
  32. Hope J. C., Sopp P., Collins R. A. and Howard C. J. 2001. Differences in the induction of CD8+ T cell responses by subpopulations of dendritic cells from afferent lymph are related to IL-1 alpha secretion. J. Leukoc. Biol. 69: 271.[Abstract/Free Full Text]
  33. Shornick L., De Togni P., Mariathasan S. et al. 1996. Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183: 1427.[Abstract/Free Full Text]
  34. Fong T. A. and Mosmann T. R. 1989. The role of IFN-gamma in delayed-type hypersensitivity mediated by Th1 clones. J. Immunol. 143: 2887.[Abstract]
  35. Magram J., Connaughton S. E., Warrier R. R. et al. 1996. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 4: 471.[CrossRef][Web of Science][Medline]
  36. Werman A., Werman-Venkert R., White R. et al. 2004. The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proc. Natl Acad. Sci. USA 101: 2434.[Abstract/Free Full Text]
  37. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A. and Bloom B. R. 1993. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178: 2249.[Abstract/Free Full Text]
  38. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G. and Orme I. M. 1993. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J. Exp. Med. 178: 2243.[Abstract/Free Full Text]
  39. Guo Z., Zhang M., An H. et al. 2003. Fas ligation induces IL-1beta-dependent maturation and IL-1beta-independent survival of dendritic cells: different roles of ERK and NF-kappaB signaling pathways. Blood 102: 4441. (Epub August14, 2003.)[Abstract/Free Full Text]
  40. Khoruts A., Osness R. E. and Jenkins M. K. 2004. IL-1 acts on antigen-presenting cells to enhance the in vivo proliferation of antigen-stimulated naive CD4 T cells via a CD28-dependent mechanism that does not involve increased expression of CD28 ligands. Eur. J. Immunol. 34: 1085.[CrossRef][Web of Science][Medline]
  41. Luft T., Jefford M., Luetjens P. et al. 2002. IL-1beta enhances CD40 ligand-mediated cytokine secretion by human dendritic cells (DC): a mechanism for T cell-independent DC activation. J. Immunol. 168: 713.[Abstract/Free Full Text]
  42. Wesa A. K. and Galy A. 2001. IL-1beta induces dendritic cells to produce IL-12. Int. Immunol. 13: 1053.[Abstract/Free Full Text]
  43. Freedman A. S., Freeman G., Whitman J., Segil J., Daley J. and Nadler L. M. 1988. Pre-exposure of human B cells to recombinant IL-1 enhances subsequent proliferation. J. Immunol. 141: 3398.[Abstract]
  44. Rousset F., Garcia E. and Banchereau J. 1991. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J. Exp. Med. 173: 705.[Abstract/Free Full Text]
  45. Liu Y. J., Cairns J. A., Holder M. J. et al. 1991. Recombinant 25-kDa CD23 and interleukin 1 alpha promote the survival of germinal center B cells: evidence for bifurcation in the development of centrocytes rescued from apoptosis. Eur. J. Immunol. 21: 1107.[Web of Science][Medline]
  46. Toellner K. M., Scheel-Toellner D., Sprenger R. et al. 1995. The human germinal centre cells, follicular dendritic cells and germinal centre T cells produce B cell-stimulating cytokines. Cytokine 7: 344.[CrossRef][Web of Science][Medline]
  47. Snapper C. M. and Paul W. E. 1987. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236: 944.[Abstract/Free Full Text]
  48. Peng S. L., Szabo S. J. and Glimcher L. H. 2002. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc. Natl Acad. Sci. USA 99: 5545.[Abstract/Free Full Text]
  49. Lagrange P. H. and Mackaness G. B. 1975. A stable form of delayed-type hypersensitivity. J. Exp. Med. 141: 82.[Abstract/Free Full Text]
  50. Koide S. L., Inaba K. and Steinman R. M. 1987. Interleukin 1 enhances T-dependent immune responses by amplifying the function of dendritic cells. J. Exp. Med. 165: 515.[Abstract/Free Full Text]
  51. Richards H. B., Satoh M., Shaw M., Libert C., Poli V. and Reeves W. H. 1998. Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 188: 985.[Abstract/Free Full Text]
  52. Eugster H. P., Frei K., Bachmann R., Bluethmann H., Lassmann H. and Fontana A. 1999. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 29: 626.[CrossRef][Web of Science][Medline]
  53. Kassiotis G. and Kollias G. 2001. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J. Exp. Med. 193: 427.[Abstract/Free Full Text]
  54. Campbell I. K., O'Donnell K., Lawlor K. E. and Wicks I. P. 2001. Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J. Clin. Invest. 107: 1519.[Web of Science][Medline]
  55. Tada Y., Ho A., Koarada S. et al. 2001. Collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor-1. Clin. Immunol. 99: 325.[CrossRef][Web of Science][Medline]
  56. Mori L., Iselin S., De Libero G. and Lesslauer W. 1996. Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J. Immunol. 157: 3178.[Abstract]
  57. Huang D., Tani M., Wang J. et al. 2002. Pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 overexpression in mice. J. Neurosci. 22: 10633.[Abstract/Free Full Text]
  58. Rand M. L., Warren J. S., Mansour M. K., Newman W. and Ringler D. J. 1996. Inhibition of T cell recruitment and cutaneous delayed-type hypersensitivity-induced inflammation with antibodies to monocyte chemoattractant protein-1. Am. J. Pathol. 148: 855.[Abstract]
  59. Kawakami K., Koguchi Y., Qureshi M. H. et al. 2000. Reduced host resistance and Th1 response to Cryptococcus neoformans in interleukin-18 deficient mice. FEMS Microbiol. Lett. 186: 121.[CrossRef][Web of Science][Medline]
  60. Cruikshank W. W., Kornfeld H. and Center D. M. 2000. Interleukin-16. J. Leukoc. Biol. 67: 757.[Abstract]
  61. Wilkinson R. J., Patel P., Llewelyn M. et al. 1999. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis. J. Exp. Med. 189: 1863.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Immunol.Home page
A. S. Almeida, P. M. Lago, N. Boechat, R. C. Huard, L. C. O. Lazzarini, A. R. Santos, M. Nociari, H. Zhu, B. M. Perez-Sweeney, H. Bang, et al.
Tuberculosis Is Associated with a Down-Modulatory Lung Immune Response That Impairs Th1-Type Immunity
J. Immunol., July 1, 2009; 183(1): 718 - 731.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Elkabets, Y. Krelin, S. Dotan, A. Cerwenka, A. Porgador, R. G. Lichtenstein, M. R. White, M. Zoller, Y. Iwakura, C. A. Dinarello, et al.
Host-Derived Interleukin-1{alpha} Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells
J. Immunol., April 15, 2009; 182(8): 4874 - 4881.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. Nakae, Y. Iwakura, H. Suto, and S. J. Galli
Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17
J. Leukoc. Biol., May 1, 2007; 81(5): 1258 - 1268.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/5/701    most recent
dxl007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Nambu, A.
Right arrow Articles by Iwakura, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nambu, A.
Right arrow Articles by Iwakura, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?