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CUTTING EDGE |



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* Section of Pulmonary and Critical Care Medicine,
Alcohol Research Center,
Gene Therapy Program, and
Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112
| Abstract |
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| Introduction |
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Our group has previously described the importance of IL-17 signaling in a murine model of Klebsiella pneumoniae pulmonary infection (4). Mice lacking the receptor for IL-17 showed a blunted G-CSF and MIP-2 response, decreased neutrophil recruitment, greater bacterial burden, and worsened mortality. Conversely, IL-17 overexpression via intratracheal (i.t.) adenoviral vector administration resulted in enhanced chemokine production, neutrophil recruitment, and survival in the same model (10).
Although the importance of IL-17 signaling in host defense against K. pneumoniae infection seems evident, the specific physiologic trigger for its expression is unclear. Others have shown that certain microbial exotoxins, lipopeptides, and mycobacterial lysates can stimulate T cells to produce IL-17 in vitro (2). We hypothesized that LPS, the major superantigen of Gram-negative bacteria, may be responsible for IL-17 production in a murine model of pneumonia. Previous work has shown that LPS signaling is via Toll-like receptor (TLR)4, a pattern recognition receptor expressed on APC throughout a vast range of species (11). To test this hypothesis, we used C3H/HeJ mice, which have a mutation in the cytoplasmic tail of TLR4 and are hence unable to signal in response to LPS (11). In this study, we show that induction of IL-17 in the lung is TLR4 dependent. Using a dendritic cell (DC) and T cell coculture system, we demonstrate that DC-derived IL-23, a recently described heterodimer consisting of a p40 subunit identical with that of IL-12 and a unique p19 subunit (12), signals the induction of IL-17 in both CD4+ and CD8+ T cells.
| Materials and Methods |
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C57BL/6, C3H/HeN (National Cancer Insitute, Frederick, MD), and C3H/HeJ, or IL-12 p35-/- (13) or p40-/- (14) mice on a C57BL/6 background (The Jackson Laboratory, Bar Harbor, ME), mice were received at 68 wk of age. K. pneumoniae strain 43816 (serotype 2) was from American Type Culture Collection (Manassas, VA). Mice were anesthetized with ketamine/xylazine, the trachea was cannulated with a 30-gauge needle, and 50 µl of bacteria (104 CFU) was injected. At 0, 4, and 16 h, animals were sacrificed, and bronchoalveolar lavage (BAL) was performed as described previously (10). Samples were frozen for later IL-17 ELISA (R&D Systems, Minneapolis, MN). Lungs were removed and homogenized in TRIzol (Life Technologies, Gaithersburg, MD), and total RNA was isolated. RNA was either subjected to real-time RT-PCR in an ABI 7700 thermocycler using TaqMan reagents (both from Applied Biosystems, Foster City, CA) for IL-17 or IL-23 p19 mRNA or analyzed on a murine genome array chip U74Av2 (Affymetrix, Santa Clara, CA). For T cell depletion experiments, animals were pretreated with i.p. anti-CD4+ (clone GK1.5; Taconic Labs, Germantown, NY) or anti-CD8+ Ab (clone 2.43; American Type Culture Collection) 4 days before bacterial challenge.
Cell preparations
DC were derived from hemopoietic progenitors of mouse bone marrow. Cells were grown in RPMI 1640 medium with 10% FBS supplemented with 100 U/ml GM-CSF and 20 ng/ml IL-4 (R&D Systems). After 1 wk, all DC preparations were >90% positive for class II MHC (I-A), CD80, and CD11c, with <1% staining for CD4, CD8, CD19, or the NK cell marker DX-5. Spleens were processed through a 40-µm filter, and red cells were lysed. Total splenic T lymphocytes were purified using magnetic labeled anti-CD90 beads, or T cell subsets were positively selected using anti-CD4 or anti-CD8 beads (Miltenyi Biotec, Auburn, CA). Purified CD4+ or CD8+ subsets were at least 95% pure and contained <1% of the other T cell population based on FACS analysis.
DC/lymphocyte coculture system
After 1 wk of maturation, 105 DC were plated in 24-well tissue culture plates. K. pneumoniae (107 CFU; 100:1 bacteria/DC ratio) were added and incubated for 24 h. T cells (5 x 105; CD90+, CD4+, or CD8+ cells) were added to the system for an additional 24 h. For experiments designed to test the need for direct physical contact between DC and T cell, we placed the T cells into a Transwell 0.4 µm polyester membrane insert (Corning, Corning, NY). Also, T cells were exposed to conditioned medium from K. pneumoniae-pulsed DC. For experiments designed to test the role of IL-23, Ab directed against mouse p40, a subunit common to IL-12 and IL-23, or isotype control, was incubated for 1 h with conditioned medium before T cell addition (R&D Systems). To exclude IL-12 neutralization as a confounder, DC from p35-/-, p40-/-, or wild-type C57BL/6 animals were harvested and cultured as above in Cell preparations. After 24 h, samples were spun, and the supernatant was assayed for IL-17. Cells were resuspended in TRIzol, and RNA was isolated for IL-17 transcript analysis. Transcript copy number was determined by comparing the cycle threshold of each unknown sample to those of a standard curve of a known quantity of murine IL-17 or p19 cDNA standards, which we have previously cloned. All RT-PCR data were normalized to 18s rRNA content, also determined by real-time RT-PCR.
Statistical analysis
Data were analyzed using StatView statistical software (Brainpower, Calabasas, CA), and the statistical significance between means of data was determined by Students t test. Significance was accepted at p < 0.05.
| Results and Discussion |
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90% reduction in IL-17 following K. pneumoniae challenge, suggesting that CD8+ T cells play a significant role in either mediating or directly producing IL-17 in this in vivo model of pneumonia.
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, IL-1
, IL-6, and IL-15. All of these manipulations failed to inhibit IL-17 elaboration by CD4+ T cells (data not shown). Given the proven cause and effect of IL-23 on in vitro IL-17 elaboration combined with the earlier rise in p19 mRNA transcripts in our in vivo pneumonia model, we speculate that IL-23 is likely a key proximal mediator of the early, physiologically important induction of IL-17 in Gram-negative pneumonia. The previous finding that only APCs concomitantly express p40 and p19 (12) and, hence, are the only cells believed capable of producing functional IL-23 underscores the importance of intact antigenic signaling via cognate receptors on APC (21). Indeed, other studies have already proven the vital role of TLR2 on IL-23 expression (22). The combination of our neutralization experiments and the time course of p19 induction in vivo supports the hypothesis that IL-23 in response to K. pneumoniae is a key proximal event leading to IL-17 production in vivo. Future experiments using p19 knockout animals will enable us to answer this question more directly.
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24 h) IL-17 elaboration in primary T cells, because IL-17 is induced rapidly in vivo in the lung after K. pneumoniae challenge (10). In this model of Gram-negative pneumonia, a critical early host response is brisk neutrophil recruitment to quickly phagocytize invading pathogens before they begin geometric multiplication. Animals unable to mount this neutrophilic response to pulmonary K. pneumoniae infection display greater lung bacterial burden, bacteremia, and death (23). Earlier work has shown a critical role of IL-17 in neutrophil chemoattraction via its up-regulation of CXC chemokines and G-CSF (3, 10, 24). Given the ability of IL-17 to induce neutrophil chemokine induction as well as granulopoiesis, it stands to reason that this cytokine likely functions as an important signal from T lymphocytes in orchestrating an augmented innate immune response to enhance pathogen clearance.
Our work proves that both CD4+ and CD8+ T cells can produce IL-17 in response to Gram-negative bacteria via TLR4 signaling, presumably by APC in the lung. It will be important to further define subpopulations of CD4+ and CD8+ T cells responsible for in vivo IL-17 production. Because IL-17 expression is not clearly dichotomized into Th1- or Th2-like expression profiles (2), it is quite possible that IL-17-producing T cells do not represent either entity of this paradigm of acquired immunity.
Despite their lacking TLR4 signaling ability, the C3H/HeJ mice nevertheless demonstrate an increase, albeit attenuated and delayed, in both IL-17 and p19 mRNA. Based on our microarray data, this finding is consistent with a delayed expression of other proinflammatory genes, including MIP-2 and IL-6, in the C3H/HeJ strain. These later time points of gene induction may be due to LPS/TLR4-independent mechanisms, such as lipopeptide (TLR2) or unmethylated CpG motif (TLR9) signaling, which remain intact in C3H/HeJ mice. In addition, by 16 h, C3H/HeJ mice suffer a greater bacterial burden in the lung compared with that of controls. This differential inflammatory stimulus may invoke other, less potent signaling pathways to become operant in the expression of IL-17. As stated, this C3H/HeJ catch-up phenomenon is seen in many other proinflammatory signals, but likely represents too little too late, given the aforementioned increase in bacterial load and earlier occurrence of death in the C3H/HeJ strain compared with the C3H/HeN.
Our data show that intact TLR4 signaling represents the early and physiologically requisite signaling pathway in the timely expression of IL-23 and IL-17 in this Gram-negative pneumonia model. Further characterization of IL-23 and other downstream T cell mediators will greatly enlighten our understanding of the early communication between innate and acquired immunity in response to bacterial challenge.
| Footnotes |
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2 Address correspondence and reprint requests to Dr. Jay Kolls, Louisiana State University Health Science Center, Clinical Sciences Research Building, Room 601, 533 Bolivar Street, New Orleans, LA 70112. E-mail address: jkolls{at}lsuhsc.edu ![]()
3 Abbreviations used in this paper: MIP-2, macrophage-inflammatory protein 2; i.t., intratracheal; TLR, Toll-like receptor; DC, dendritic cell; BAL, bronchoalveolar lavage. ![]()
Received for publication December 2, 2002. Accepted for publication March 6, 2003.
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G. Piskin, R. M. R. Sylva-Steenland, J. D. Bos, and M. B. M. Teunissen In Vitro and In Situ Expression of IL-23 by Keratinocytes in Healthy Skin and Psoriasis Lesions: Enhanced Expression in Psoriatic Skin J. Immunol., February 1, 2006; 176(3): 1908 - 1915. [Abstract] [Full Text] [PDF] |
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M. A. Kleinschek, U. Muller, S. J. Brodie, W. Stenzel, G. Kohler, W. M. Blumenschein, R. K. Straubinger, T. McClanahan, R. A. Kastelein, and G. Alber IL-23 Enhances the Inflammatory Cell Response in Cryptococcus neoformans Infection and Induces a Cytokine Pattern Distinct from IL-12 J. Immunol., January 15, 2006; 176(2): 1098 - 1106. [Abstract] [Full Text] [PDF] |
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C.-Y. Kao, F. Huang, Y. Chen, P. Thai, S. Wachi, C. Kim, L. Tam, and R. Wu Up-Regulation of CC Chemokine Ligand 20 Expression in Human Airway Epithelium by IL-17 through a JAK-Independent but MEK/NF-{kappa}B-Dependent Signaling Pathway J. Immunol., November 15, 2005; 175(10): 6676 - 6685. [Abstract] [Full Text] [PDF] |
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A. M. C. van Rossum, E. S. Lysenko, and J. N. Weiser Host and Bacterial Factors Contributing to the Clearance of Colonization by Streptococcus pneumoniae in a Murine Model Infect. Immun., November 1, 2005; 73(11): 7718 - 7726. [Abstract] [Full Text] [PDF] |
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K. I. Happel, P. J. Dubin, M. Zheng, N. Ghilardi, C. Lockhart, L. J. Quinton, A. R. Odden, J. E. Shellito, G. J. Bagby, S. Nelson, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae J. Exp. Med., September 19, 2005; 202(6): 761 - 769. [Abstract] [Full Text] [PDF] |
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K. I. Happel, E. A. Lockhart, C. M. Mason, E. Porretta, E. Keoshkerian, A. R. Odden, S. Nelson, and A. J. Ramsay Pulmonary Interleukin-23 Gene Delivery Increases Local T-Cell Immunity and Controls Growth of Mycobacterium tuberculosis in the Lungs Infect. Immun., September 1, 2005; 73(9): 5782 - 5788. [Abstract] [Full Text] [PDF] |
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S. A. Khader, J. E. Pearl, K. Sakamoto, L. Gilmartin, G. K. Bell, D. M. Jelley-Gibbs, N. Ghilardi, F. deSauvage, and A. M. Cooper IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-{gamma} Responses if IL-12p70 Is Available J. Immunol., July 15, 2005; 175(2): 788 - 795. [Abstract] [Full Text] [PDF] |
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F. McAllister, A. Henry, J. L. Kreindler, P. J. Dubin, L. Ulrich, C. Steele, J. D. Finder, J. M. Pilewski, B. M. Carreno, S. J. Goldman, et al. Role of IL-17A, IL-17F, and the IL-17 Receptor in Regulating Growth-Related Oncogene-{alpha} and Granulocyte Colony-Stimulating Factor in Bronchial Epithelium: Implications for Airway Inflammation in Cystic Fibrosis J. Immunol., July 1, 2005; 175(1): 404 - 412. [Abstract] [Full Text] [PDF] |
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N. Schuetze, S. Schoeneberger, U. Mueller, M. A. Freudenberg, G. Alber, and R. K. Straubinger IL-12 family members: differential kinetics of their TLR4-mediated induction by Salmonella Enteritidis and the impact of IL-10 in bone marrow-derived macrophages Int. Immunol., May 1, 2005; 17(5): 649 - 659. [Abstract] [Full Text] [PDF] |
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R. Malley, K. Trzcinski, A. Srivastava, C. M. Thompson, P. W. Anderson, and M. Lipsitch CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization PNAS, March 29, 2005; 102(13): 4848 - 4853. [Abstract] [Full Text] [PDF] |
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F. Shen, M. J. Ruddy, P. Plamondon, and S. L. Gaffen Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells J. Leukoc. Biol., March 1, 2005; 77(3): 388 - 399. [Abstract] [Full Text] [PDF] |
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C. L. Langrish, Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua IL-23 drives a pathogenic T cell population that induces autoimmune inflammation J. Exp. Med., January 18, 2005; 201(2): 233 - 240. [Abstract] [Full Text] [PDF] |
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A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [Abstract] [Full Text] [PDF] |
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J. R. Schurr, E. Young, P. Byrne, C. Steele, J. E. Shellito, and J. K. Kolls Central Role of Toll-Like Receptor 4 Signaling and Host Defense in Experimental Pneumonia Caused by Gram-Negative Bacteria Infect. Immun., January 1, 2005; 73(1): 532 - 545. [Abstract] [Full Text] [PDF] |
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X. K. Liu, X. Lin, and S. L. Gaffen Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17 J. Biol. Chem., December 10, 2004; 279(50): 52762 - 52771. [Abstract] [Full Text] [PDF] |
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C.-Y. Kao, Y. Chen, P. Thai, S. Wachi, F. Huang, C. Kim, R. W. Harper, and R. Wu IL-17 Markedly Up-Regulates {beta}-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-{kappa}B Signaling Pathways J. Immunol., September 1, 2004; 173(5): 3482 - 3491. [Abstract] [Full Text] [PDF] |
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L. A. Lieberman, F. Cardillo, A. M. Owyang, D. M. Rennick, D. J. Cua, R. A. Kastelein, and C. A. Hunter IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-12 J. Immunol., August 1, 2004; 173(3): 1887 - 1893. [Abstract] [Full Text] [PDF] |
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N. Ghilardi, N. Kljavin, Q. Chen, S. Lucas, A. L. Gurney, and F. J. de Sauvage Compromised Humoral and Delayed-Type Hypersensitivity Responses in IL-23-Deficient Mice J. Immunol., March 1, 2004; 172(5): 2827 - 2833. [Abstract] [Full Text] [PDF] |
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M. A. Olman, K. E. White, L. B. Ware, W. L. Simmons, E. N. Benveniste, S. Zhu, J. Pugin, and M. A. Matthay Pulmonary Edema Fluid from Patients with Early Lung Injury Stimulates Fibroblast Proliferation through IL-1{beta}-Induced IL-6 Expression J. Immunol., February 15, 2004; 172(4): 2668 - 2677. [Abstract] [Full Text] [PDF] |
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