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Cutting Edge: IL-18-Transgenic Mice: In Vivo Evidence of a Broad Role for IL-18 in Modulating Immune Function

Tomoaki Hoshino^1,*, Yusuke Kawase^2,, Masaki Okamoto^2,*, Koichi Yokota, Kohichiro Yoshino, Ken-ichi Yamamura, Jun-ichi Miyazaki, Howard A. Young^¶ and Kotaro Oizumi^3,*

^* Department of Internal Medicine 1, Kurume University, Kurume, Japan; Research and Development Division, R&D Laboratories, Nippon Organon K.K., Osaka, Japan; Institute of Molecular Embryology Genetics, Kumamoto University, Kumamoto, Japan; Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka, Japan; and ^¶ Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Frederick, MD 21702

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
IL-18 has been shown to be a strong cofactor for Th1 T cell development. However, we previously demonstrated that when IL-18 was combined with IL-2, there was a synergistic induction of a Th2 cytokine, IL-13, in both T and NK cells. More recently, we and other groups have reported that IL-18 can potentially induce IgE, IgG1, and Th2 cytokine production in murine experimental models. Here, we report on the generation of IL-18-transgenic (Tg) mice in which mature mouse IL-18 cDNA was expressed. CD8⁺CD44^high T cells and macrophages were increased, but B cells were decreased in these mice while serum IgE, IgG1, IL-4, and IFN- levels were significantly increased. Splenic T cells in IL-18 Tg mice produced higher levels of IFN-, IL-4, IL-5, and IL-13 than control wild-type mice. Thus, aberrant expression of IL-18 in vivo results in the increased production of both Th1 and Th2 cytokines.

	Introduction

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Interleukin 18 was discovered as IFN--inducing factor and acts in synergy with IL-12 to enhance IFN- gene expression (1, 2, 3). IL-18 also induces Fas ligand, GM-CSF, proinflammatory cytokines TNF and IL-1, and chemokines such as IL-8 and macrophage-inflammatory protein 1 (2, 3, 4, 5). IL-18 shares biological similarity with IL-12, a strong Th1 inducer, although IL-18 is not structurally related to IL-12 (1, 2, 3). IL-18, like IL-12, augments NK activity through the induction of constitutively expressed IL-18R on NK cells (6). Moreover, a previous study reported that IL-18R (IL-1R-related protein) is selectively expressed on the surface of Th1 but not Th2 cells (7). Based on these reports, IL-18 was thought to be a strong cofactor for Th1 cell development (2, 3, 8). However, we have demonstrated that IL-18, in combination with IL-2 but not with IL-12, can be a strong cofactor for the expression of a Th2 cytokine, IL-13, in T cells and in a unique NK population (9, 10). More recently, we and other groups have reported that IL-18 can potentially induce Th2 cytokines (IL-4, IL-5, IL-10, IL-13) and IgE and IgG1 production (11, 12, 13, 14, 15, 16), suggesting that IL-18 can act as a cofactor for both Th1 and Th2 cell development.

IL-18 is intracellularly produced from a biologically inactivated precursor; pro-IL-18 and mature IL-18 are secreted after the cleavage of pro-IL-18 by caspase-1, originally identified as IL-1-converting enzyme (2, 3). It has been reported that pro-IL-18 mRNA is expressed in a wide range of cells, including Kupffer cells, macrophages, T cells, B cells, osteoblasts, keratinocytes, dendritic cells, astrocytes, and microglia (2, 3). In fact, pro-IL-18 protein is produced in various cells including Kupffer cells, macrophages, and keratinocytes, whereas mature IL-18 is only weakly detected in mouse sera or tissues (1, 2, 3). To test the biological consequences of IL-18 overexpression in vivo, we generated IL-18-transgenic (Tg)⁴ mice in which B and mature T cells could express mature mouse IL-18 cDNA fused with the signal peptide of the mouse Ig -chain under the control of mouse Ig promoter. The results presented here demonstrate that overexpression of IL-18 can induce high IgE, IgG1, IL-4, and IFN- expression in vivo. Thus, aberrant in vivo IL-18 expression results in the expression of cytokines that affect both Th1-and Th2-type development, suggesting that the clinical use of this IL may result in unexpected physiological consequences.

	Materials and Methods

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Transfection

Complementary DNAs encoding the signal peptide (SP) from the V-J2-C region of the mouse Ig -chain (17) fused with mature mouse IL-18 cDNA (1) and mouse IL-18 cDNA were generated by PCR using mouse pro-IL-18 cDNA (18), kindly obtained from Kiyoshi Takeda (Osaka University, Osaka, Japan). Amplified DNA was subcloned into the pCR2.1 vector (Invitrogen, Carlsbad, CA) and sequenced. Then mature mouse IL-18 cDNA encoding SP and mature mouse IL-18 were subcloned into pcdEF3 vector (19), kindly obtained from Jerome Langer (Robert Wood Johnson Medical School, Piscataway, NJ). Plasmid DNA (0.5–2 µg) was transfected into 3 x 10⁵ 293 cells by FuGene 6 (Boehringer Mannheim, Mannheim, Germany). The cell supernatants and cell lyses were analyzed using a murine (m) IL-18 ELISA kit (MBL, Nagoya, Japan) and Western blotting, respectively, 48 h after the transfection. Rat anti-mIL-18 mAb (39-3F; MBL) or rabbit anti-mIL-18 Ab, kindly obtained from Charles A. Dinarello (University of Colorado Health Sciences Center), was used for Western blotting.

Generation of a Tg mouse expressing mature mouse IL-18

Mature mouse IL-18 cDNA encoding SP (IL-18SP) were generated and subcloned into the pCR2.1 vector as describe above. The EcoRI-digested DNA fragment was inserted into the EcoRI site of the pEµIgH vector (20) containing the human Eµ enhancer and mouse IgVH promoter. The linear pEµIgH/IL-18SP DNA fragment was injected into fertilized eggs of B6 mice at Oriental Bio Service (Kyoto, Japan). Hemizygous Tg mice were generated by mating founder mice with wild-type (wt) B6 mice. The offspring mice were screened by PCR and Southern blotting analyses using tail DNA as previously reported (21), and IL-18 expression in sera was confirmed by the mouse IL-18 ELISA.

Surface Ag and intracellular analysis by flow cytometry

Three-color analysis was performed using a FACScan (22). For intracellular cytokine staining (10), isolated spleen cells from Tg and wt mice were stimulated with PMA (20 ng/ml) plus ionomycin (500 ng/ml) for 4 h in the presence of 4 µM monensin at 37°C. Then cells were further stained with FITC-anti-mIL-4, FITC-anti-mIL-5, PE-anti-mIFN-, and/or control isotype-matched mAb. A total of >30,000 cells was analyzed in each FACS analysis.

Statistical analysis

The difference between groups was analyzed by Wilcoxon signed rank test and, if appropriate, by paired t test. Values of p < 0.05 were considered to be significant.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Expression of the mature mouse IL-18 transgene in the IL-18 Tg mouse

First, transfection experiments were conducted to confirm whether the transgene construct could induce an optimal secretion of mature IL-18 in vitro. Expression from two constructs was analyzed: one was mature mouse IL-18 cDNA fused to the SP of the mouse Ig -chain, and the other was mature mouse IL-18 cDNA without the SP used as a control. These two cDNA constructs were subcloned into the pcdEF3 vector containing the human elongation factor (EF) 1 promoter (19) and were designated as pEF-IL-18SP and pEF-IL-18, respectively. Of these expression constructs, 0.5–2 µg was transiently transfected into 293 cells. Mature IL-18 was found in the supernatants of the pEF-IL-18SP but not in pEF-IL-18-transfected 293 cells (Fig. 1A). Western blotting analysis showed both pEF-IL-18SP- and pEF-IL-18-transfected 293 cells produced mature IL-18 protein of 18 kDa (data not shown). Based on the expression of soluble IL-18, we generated an IL-18 Tg mouse under the control of murine Ig promoter and human Ig enhancer. The construct design is shown in Fig. 1B. We established 5 founders (no. 8 strain male, no. 13 male, no. 14 male, no. 23 female, and no. 24 female) that showed transgene integration. For most studies shown below, we used hemizygous mice from the no. 8 founder. ELISA analysis showed high serum IL-18 levels were found in all IL-18 Tg founders and hemizygous mice derived from these founders, whereas mean serum IL-18 levels of control wt B6 mice were <0.26 ng/ml. Large amounts of mature IL-18 (18 kDa) protein were detected in the sera of IL-18 Tg mouse by Western blot analysis (Fig. 1C).

View larger version (24K): [in this window] [in a new window]   FIGURE 1. Generation of the IL-18 Tg mouse. A, 0.5–2 µg of construct bearing mature IL-18 cDNA fused with the SP from the mouse Ig -chain (IL-18(SP)) or mature IL-18 cDNA without the SP (IL-18) under the control of the human EF-1 promoter (pcdEF3 vector (19 )) was transiently transfected into 3 x 105 293 cells utilizing FuGene 6 (Boehringer Mannheim). The supernatants were analyzed 48 h after the transfection using a mIL-18 ELISA kit. ND, not detectable. B, pEµIgH vector encoding human Eµ enhancer and mouse IgVH promoter (20 ) was used to generate IL-18 Tg mice. A schematic design of the cDNA construct used to generate the IL-18 Tg mouse is shown. C, Serum IL-18 levels in IL-18 Tg (no. 8 strain) and littermate wt C57BL/6 mice (n = 4 each) were measured using a mIL-18 ELISA kit (MBL). Western blotting analysis for detecting serum mature IL-18 (18 kDa) in the IL-18 Tg and wt mice was performed.

Ten- to 14-wk-old Tg and control mice (n = 4 each) were analyzed by flow cytometry, and a representative staining pattern is shown in Fig. 2A. We found that the mean total number of cells in the Tg and wt mice was 1.0 x 10⁸ and 1.2 x 10⁸ cells/spleen, respectively. The mean percentage of CD8⁺CD4^- but not CD4⁺CD8^- T cells was significantly (p < 0.05) increased in the Tg mice when compared with wt mice (CD8⁺CD4^- T cells in Tg 23.3% vs wt 12.7%). Spleen CD8⁺ T cells in the Tg mice showed a high CD44 (CD44^high) CD25 (IL-2R^-) phenotype, whereas 25% of CD4⁺ T cells in the Tg mice expressed CD25 (data not shown). In contrast, the percentage of CD19⁺B220⁺IgM⁺ B cells was significantly (p < 0.05) decreased when compared with wt mice (Tg 32.4% vs wt 54.4%). The percentages of CD3^- NK1.1⁺ DX5⁺ NK cells, CD3⁺ NK1.1⁺ DX5⁺ (NK-T), and CD3⁺ TCR⁺ cells in Tg mice were 2–4%, and no significant difference was found when compared with wt mice. CD3 and TCR expression on T cells in the Tg mice was weaker than that observed in wt mice (data not shown). Moreover, the Gr1⁺ CD11b (Mac1)⁺ F4/80⁺ population was increased in the Tg mice. These results indicate that memory-phenotype CD8⁺CD44^high T cell and Gr1⁺ CD11b (Mac1)⁺ F4/80⁺ macrophage or granulocyte populations were selectively expanded in the spleen of IL-18 Tg mice.

View larger version (69K): [in this window] [in a new window]   FIGURE 2. CD8+CD44high T cells and macrophages were increased, but B cells were decreased in the IL-18 Tg mouse. A, Spleen cells were isolated from IL-18 Tg and littermate wt mice and stained with FITC-, PE-, or CyChrome-conjugated mAb in the presence of anti-mCD16/CD32 mAb. B, Spleen CD4+ T cells can express IL-4, IL-5, and IFN- in the IL-18 Tg mouse. Isolated spleen cells were cultured with PMA (20 ng/ml) plus ionomycin (500 ng/ml) for 4 h, washed, and stained with CyChrome-conjugated anti-mCD4 or anti-mCD8 mAb in the presence of anti-mCD16/CD32 mAb. Then cells were fixed, permeabilized, and stained with PE-anti-mIFN- mAb and FITC-anti-mIL-4 mAb or FITC-anti-mIL-5 (PharMingen, San Diego, CA). Three-color analysis was performed for analyzing cytoplasmic IL-4, IL-5, and IFN- expression in CD4+ and CD8+ T cells.

CD4⁺ T cells express intracellular IL-4, IL-5, and IFN- in an IL-18 Tg mouse

Naive spleen cells isolated from Tg and wt mice were stimulated with PMA plus ionomycin for 4 h and analyzed for cytoplasmic IL-4, IL-5, and IFN- expression in CD4⁺ and CD8⁺ T cells (Fig. 2B). The intracellular staining revealed that CD4⁺ T cells in Tg mice strongly expressed IFN- and the type 2 cytokine IL-5, but weakly expressed IL-4. Although CD8⁺ T cells barely expressed IL-4 in both Tg and wt mice, CD8⁺ T cells in Tg mice strongly expressed IFN- and IL-5. We could not analyze IL-13 expression on CD4⁺ and CD8⁺ T cells, as there is no commercial reagent for intracellular staining of mIL-13.

IL-4, IL-5, IL-13, and IFN- production in vitro culture in an IL-18 Tg mouse

As we have previously reported (9, 10, 11), naive spleen lymphocytes from wt mice did not induce the Th2 cytokines, IL-4, IL-5, and IL-13 (<40 pg/ml), but induced IFN- production in response to PMA plus ionomycin, anti-CD3 mAb, IL-2 alone, or anti-CD3 mAb plus IL-2 (Table I). Surprisingly, naive spleen lymphocytes from Tg mice did demonstrate greater production of IFN-, IL-5, and IL-13 when compared with wt mice in response to these stimuli. In contrast, IL-4 production was not significantly increased when supernatants from the Tg mouse spleen cells and control cells were compared. The same observation was found in the in vitro culture using nylon wool column-passed spleen lymphocytes where equivalent numbers of CD3⁺ T cells are present in both Tg and wt mice (data not shown). Our present study supports previous reports which demonstrate that IL-13 and IL-5 may be more affected by IL-18 than IL-4 (11, 12, 13).

Serum levels of IgE, IgG1, IL-4, and IFN- were increased in the IL-18 Tg mouse

We analyzed serum IgE, IgG1, IL-4, and IFN- levels in 9-wk-old Tg and wt mice (Fig. 3). Serum IgE levels of Tg mice were significantly (p = 0.01) higher than those observed in control wt B6 mice (<0.4 µg/ml), whereas serum IgG1 levels were not significantly increased. Surprisingly, serum IgG1 levels in Tg mice gradually increased with aging. Serum IgG1 levels in 15-wk-old Tg mice were significantly (p = 0.02; 3-fold) higher than those observed in 9-wk-old Tg mice and were also significantly (p = 0.02) higher than in 15-wk-old wt mice. Normally, serum IL-4 and IFN- levels were below the detectable level. Serum IL-4 levels were significantly (p = 0.04) increased in Tg mice, although IL-4 expression and production in the spleen cells of IL-18 Tg mice was weak (Table I and Fig. 2B). Yoshimoto et al. (12) previously reported that IL-18 induced IL-4 production by basophils. These results suggest that other lymphoid organs can produce IL-4 in Tg mice. Serum IFN- levels in Tg mice were significantly (p = 0.04) increased compared with control wt mice, consistent with those observed in intracellular staining and in vitro analyses. It is also possible that increased IgE and IgG1 levels and cytokines levels were influenced by the fact that the IL-18 Tg mice contain more T cells and are more endogenously activated in vivo. Further analysis is needed to test this hypothesis.

View larger version (23K): [in this window] [in a new window]   FIGURE 3. Serum IgE, IgG1, IL-4, and IFN- levels were increased in the IL-18 Tg mouse. A, Serum IgE, IL-4, and IFN- levels in 9-wk-old IL-18 Tg and littermate wt mice (n = 4 each) were measured by ELISA as previously reported (11 ). Serum IgE, IL-4, and IFN- levels in wt mice were <0.4 µg/ml, <20 pg/ml, and 20 pg/ml, respectively. B, Serum IgG1 levels in IL-18 Tg mice gradually increase with aging. Serum IgG1 levels in IL-18 Tg and littermate wt mice (n = 3 each) were measured in mice 9 to 15 wk old. Serum IgG1 levels in 15-wk-old IL-18 Tg mice were significantly (p = 0.02) higher in 9-wk-old IL-18 Tg mice and were also significantly (p = 0.02) higher than in 15-wk-old wt control mice.

CD8⁺ T cells can be classified into two distinct effector cell types based on their cytokine-secreting profiles following Ag stimulation. Type 1 CD8⁺ T cells (Tc1) produce IL-2, IFN-, and TNF-, whereas type 2 CD8⁺ T cells (Tc2) predominantly express IL-4, IL-5, and IL-10 (8). We observed increased numbers of CD8⁺CD3⁺ T cells in the spleen of IL-18 Tg mice. Intracellular staining analysis revealed that CD8⁺ T cells in Tg mice strongly expressed IFN- and IL-5, but barely expressed IL-4 when stimulated with PMA plus ionomycin (Fig. 2B). These results suggest that the increased CD8⁺ T cells in Tg mice are neither Tc1 nor Tc2 like as they express both IFN- and IL-5.

Perturbation of T cell and thymocyte development was previously reported in IL-4 and IL-13 Tg mice (24). Previously, we established IFN- Tg mice in which bone marrow and thymocytes were expressing IFN-, resulting in the absence of all B cells, T cell lineage alterations, and hemopoietic progenitor deficiencies (21). In the IL-18 Tg mice, while CD8⁺CD44^high T cells and F4/80⁺ macrophages were induced, B cells were reduced, when compared with wt mice. Thus, we hypothesize that the changes in lymphocyte populations in the IL-18 Tg mice are due to in vivo induction of IFN-, IL-4, IL-13, and other cytokines or chemokines. Cross-breeding these mice with mice lacking specific cytokine genes will be necessary to test this model.

In summary, our data demonstrate that the expression of IL-18 in vivo can modulate IgE, IgG1, IFN-, and Th2 cytokines and T cell, B cell, and macrophage development. IL-18 Tg animals represent an important tool for defining the in vivo and in vitro regulation of Th1 and Th2 development and demonstrate the importance of analyzing the effects of cytokine expression in murine models before proceeding to human clinical trials.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Tomoaki Hoshino, Department of Internal Medicine 1, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail address: hoshino{at}med.kurume-u.ac.jp

² Y.K. and M.O. contributed equally to this work.

³ Current address: TB Laboratory, University Teaching Hospital, Zambia.

⁴ Abbreviations used in this paper: Tg, transgenic; SP, signal peptide; m, murine; wt, wild type; EF, elongation factor.

Received for publication March 5, 2001. Accepted for publication April 17, 2001.

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