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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 9-11, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0255PS

Perspective

Interleukin-17

An Emerging Role in Lung Inflammation

Jay K. Kolls, Suzanne T. Kanaly and Alistair J. Ramsay

Department of Medicine, Section of Pulmonary and Critical Care Medicine, Gene Therapy Program, LSU Health Sciences Center, New Orleans, Louisiana; and Amgen, Seattle, Washington

Address correspondence to: Jay K. Kolls, M.D., Gene Therapy Program, Louisiana State University Health Sciences Center of New Orleans, 533 Bolivar CRSB, New Orleans, LA 70112. E-mail: jkolls{at}lsuhsc.edu

Abbreviations: airways hyperresponsiveness, AHR • delayed type hypersensitivity, DTH • interleukin, IL • ovalbumin, OVA

Interleukin (IL)-17 is a proinflammatory cytokine, produced by T cells, that regulates pulmonary neutrophil emigration in the context of both local gram-negative bacterial infection and now, in a report by Hellings and coworkers in this issue of the AJRCMB, to antigenic stimuli (1).

IL-17 is a proinflammatory cytokine expressed by activated memory CD4+ T cells. It was initially described and cloned by Golstein and coworkers and named CTLA8 (2). IL-17 shows 58% homology with an open reading frame of the T-lymphotropic herpesvirus samirii (viral IL-17), and is the prototypic member of a family of IL-17–like cytokines named IL-17A-F (3, 4). These cytokines are secreted proteins ranging from 150–180 amino acids and circulate as dimers. It appears that IL-17 family members signal through a family of unique cognate receptors; however, this remains to be fully elucidated. IL-17 signals through the IL-17 R (3), a Type I transmembrane protein that is fairly ubiquitously expressed in tissues; however, our laboratory has been unable to detect IL-17 R expression in murine tissue macrophages, such as alveolar macrophages (Kolls and colleagues, unpublished observations). The relatively low affinity of IL-17 with its receptor (Ka values between 2 x 107 and 2 x 108 M-1) (5), despite its ability to signal at low concentrations, has caused speculation about the existence of additional IL-17 receptors. However, mice with a homozygous deletion of the IL-17 R demonstrate no binding of an IL-17Fc fusion protein (6) and fail to show a granulopoietic response to IL-17 overexpression using adenoviral-mediated gene transfer (unpublished observations). Thus data to date suggest that this is the only receptor for IL-17.

IL-17 has been found to be elevated in a variety of inflammatory conditions including Rheumatoid arthritis (7, 8), gram-negative bacterial pneumonia (6, 9), and asthma (10, 11). Moreover, overexpression of IL-17 or the administration of recombinant IL-17 in the lung results in neutrophil emigration and the induction of both CXC chemokines (12), which recruit neutrophils to the airway as well as granulopoietic factors (such as granulocyte colony-stimulating factor) that can lead to increase in both mature neutrophils and neutrophil progenitor in the spleen and bone marrow (6) (Table 1). IL-17 may also downregulate innate antiviral immune responses. Vaccinia virus vectors encoding this factor displayed increased virulence, most likely through inhibition of antiviral natural killer cell cytotoxicity (13), a feature previously observed following infection with recombinant poxviruses expressing the Th2 cytokines IL-4 (14) or IL-10 (15). Interestingly, IL-17 also skewed antiviral antibody production toward IgG1 and IgA isotypes, suggestive of a Th2-like response to infection.


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  		TABLE 1 Genes induced in the lung by IL-17 that control granulopoiesis/neutrophil migration

 
The cytoplasmic domain of the IL-17 receptor lacks conserved signaling domains with other cytokine receptors (16), and thus the signaling pathway of IL-17 remains unclear. IL-17 has been reported to activate all three classes of MAP kinases, including ERK1 and ERK2, JNK, and P38 (17–19). The IL-17–induced activation of the MAPK pathway in bronchial epithelial cells results in the production of IL-6 and the CXC chemokine IL-8 in vitro, which is one likely mechanism by which recombinant IL-17 can induce the recruitment of neutrophils in the lung (12).

More recently, the role of IL-17 in regulating lung inflammation has been better defined through neutralization studies or using mice with a homozygous deletion of the ligand (20) or receptor (6). Mice with a homozygous deletion of the IL-17 receptor have markedly diminished recruitment of neutrophils into the lung in response to a challenge with a gram-negative pathogen (6). This is likely due to decreased CXC chemokine expression, as well as the production of granulopoietic factors such as G-CSF and stem cell factor (6, 21). Moreover, these mice fail to mount an increase in splenic neutrophil progenitors, suggesting that local IL-17 produced in the lung may also regulate systemic granulopoietic responses (6). In this model system, IL-17 is induced relatively rapidly with detectable mRNA levels by 12 h after bacterial challenge and detectable protein in the lung by 16 h. These data suggest that IL-17 is involved in the innate immune response to gram-negative bacteria. Moreover, in this model, both CD4+ and CD8+ T cells contribute to lung IL-17 production (our unpublished observations). The role of IL-17 in antigen-induced adaptive immune responses is the focus of the paper by Hellings and coworkers in this issue of the AJRCMB (1).

Hellings and coworkers neutralized IL-17 during the allergen challenge phase of a chronic ovalbumin (OVA)-induced Th2 lung inflammation model. Interestingly, IL-17 mRNA was induced rapidly in an antigen-specific fashion upon re-challenge in sensitized mice, whereas anti–IL-17 administered after sensitization (but before re-exposure) resulted in a significant reduction in neutrophil recruitment into the lung. Of note, neutralization of IL-17 had similar potency in blocking OVA-induced neutrophil recruitment as pharmacologic doses of dexamethasone (1). In contrast to neutrophil recruitment, lung eosinophilic inflammation was greater in OVA-challenged mice treated with anti–IL-17, and this enhanced eosinophilic inflammatory response was associated with higher IL-5 levels in blood and bronchoalveolar lavage fluid (1). These data were confirmed with more chronic administration of anti–IL-17 during primary allergen challenge. Furthermore, neutralization of IL-17 had systemic effects as had been observed in IL-17 R knockout mice challenged with gram-negative bacteria (6). Specifically, anti–IL-17 also reduced neutrophils in bone marrow and spleen (1). Taken together, these findings suggest that IL-17 appears to play a critical role in regulating neutrophil emigration and systemic granulopoietic responses to both pulmonary bacterial and allergen challenges. Whether this is due to emigration of IL-17 from the lung, and/or solely due to local induction of factors such as G-CSF that can emigrate from the pulmonary compartment (22), remains unclear. It is important to note that baseline granulopoiesis is not altered in IL-17 R knockout mice (6).

Recently, mice with a homozygous deletion of IL-17 have been reported (20). T cells from these mice fail to produce IL-17 after stimulation with PMA/Ionomycin, but retain normal in vitro T cell proliferation responses (20). These mice showed significantly reduced Th1-mediated delayed type hypersensitivity (DTH) responses and an attenuated T cell proliferative response to OVA sensitization with Alum (20). Interestingly, airways hyperresponsiveness (AHR) was not attenuated after aerosolized OVA challenges, nor was IL-4 or IL-5 production in the lung, results similar to those in the study by Hellings and colleagues here in the AJRCMB. To divorce the effect of adjuvant, the investigators repeated studies using OVA T cell receptor transgenics, and in this model, AHR to methacholine was reduced in OVA-challenged IL-17-/- mice.

Taken together, these studies suggest that IL-17 may be an attractive target for neutrophil-dominated inflammatory responses in the lung. However, several caveats for its potential targeting in asthma should be noted. First, the significance of exacerbating eosinophilic lung inflammation needs to be clarified. Data from IL-17-/- mice suggest that this may be adjuvant-induced; however, these mice have abnormal IL-17 responses through development of an immune response. Data from the Hellings study may be more relevant to clinical disease, where an immune response is established and one wishes to antagonize the response to subsequent exposure. Thus, studies are needed to more closely examine the role of IL-17 in regulation of IL-4, IL-13, AHR, and submucosal fibrosis. Second, because IL-17 is critical to host defense against gram-negative bacteria, neutralizing IL-17 activity may be fraught with complications of immunosuppression. These effects may be mitigated by the development of strategies to antagonize IL-17 activity in a controlled and compartmentalized fashion. Finally, it is important to note that other members of the IL-17 family such as IL-17C, IL-17F, or IL-25 (IL-17E) (23, 24) may be targets for asthma intervention as well, particularly because IL-17E or IL-25 appears critical to the induction of IL-4, IL-13, and AHR. Despite these caveats, IL-17 may be an attractive target for diseases such as chronic obstructive pulmonary disease (25, 26) or cystic fibrosis (27), where recruited neutrophils are critical mediators of lung injury.

Received in original form November 20, 2002


   References
Top
 References
 

  1. Hellings, P. W., A. Kasran, Z. Liu, P. Vandekerckhove, A. Wuyts, L. Overbergh, C. Mathieu, and J. L. Ceuppens. 2003. Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am. J. Respir. Cell Mol. Biol. 28:42–50.[Abstract/Free Full Text]
  2. Rouvier, E., M. F. Luciani, M. G. Mattei, F. Denizot, and P. Golstein. 1993. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150:5445–5456.[Abstract]
  3. Yao, Z., W. C. Fanslow, M. F. Seldin, A.-M. Rousseau, S. L. Painter, M. R. Comeau, J. I. Cohen, and M. K. Spriggs. 1995. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to novel cytokine receptor. Immunity 3:811–821.[CrossRef][Medline]
  4. Aggarwal, S., and A. L. Gurney. 2002. IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71:1–8.[Abstract/Free Full Text]
  5. Yao, Z., M. K. Spriggs, J. M. Derry, L. Strockbine, L. S. Park, T. VandenBos, J. D. Zappone, S. L. Painter, and R. J. Armitage. 1997. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine 9:794–800.[CrossRef][Medline]
  6. Ye, P., F. H. Rodriguez, S. Kanaly, K. L. Stocking, J. Schurr, P. Schwarzenberger, P. Oliver, W. Huang, P. Zhang, J. Zhang, J. E. Shellito, G. J. Bagby, S. Nelson, K. Charrier, J. J. Peschon, and J. K. Kolls. 2001. Requirement of interleukin 17 receptor signaling for lung cxc chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194:519–528.[Abstract/Free Full Text]
  7. Chabaud, M., J. M. Durand, N. Buchs, F. Fossiez, G. Page, L. Frappart, and P. Miossec. 1999. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 42:963–970.[CrossRef][Medline]
  8. Lubberts, E., L. A. Joosten, B. Oppers, B. L. Van Den, C. J. Coenen-De Roo, J. K. Kolls, P. Schwarzenberger, F. A. van De Loo, and W. B. Van den Berg. 2001. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J. Immunol. 167:1004–1013.[Abstract/Free Full Text]
  9. Ye, P., P. B. Garvey, P. Zhang, S. Nelson, G. Bagby, W. R. Summer, P. Schwarzenberger, J. E. Shellito, and J. K. Kolls. 2001. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am. J. Respir. Cell Mol. Biol. 25:335–340.[Abstract/Free Full Text]
  10. Molet, S., Q. Hamid, F. Davoine, E. Nutku, R. Taha, N. Page, R. Olivenstein, J. Elias, and J. Chakir. 2001. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol. 108:430–438.[CrossRef][Medline]
  11. Linden, A. 2001. Role of interleukin-17 and the neutrophil in asthma. Int. Arch. Allergy Immunol. 126:179–184.[CrossRef][Medline]
  12. Laan, M., Z. H. Cui, H. Hoshino, J. Lotvall, M. Sjostrand, D. C. Gruenert, B. E. Skoogh, and A. Linden. 1999. Neutrophil recruitment by human IL-17 via C–X-C chemokine release in the airways. J. Immunol. 162:2347–2352.[Abstract/Free Full Text]
  13. Patera, A., L. Pesnicak, J. Bertin, and J. Cohen. 2002. Interleukin 17 modulates the immune response to vaccinia virus infection. Virology 299:56–63.[CrossRef][Medline]
  14. Jackson, R. J., A. J. Ramsay, C. D. Christensen, S. Beaton, D. F. Hall, and I. A. Ramshaw. 2001. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J. Virol. 75:1205–1210.[Abstract/Free Full Text]
  15. Kurilla, M. G., S. Swaminathan, R. M. Welsh, E. Kieff, and R. R. Brutkiewicz. 1993. Effects of virally expressed interleukin-10 on vaccinia virus infection in mice. J. Virol. 67:7623–7628.[Abstract/Free Full Text]
  16. Spriggs, M. K. 1997. Interleukin-17 and its receptor. J. Clin. Immunol. 17:366–369.[CrossRef][Medline]
  17. Awane, M., P. G. Andres, D. J. Li, and H. C. Reinecker. 1999. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J. Immunol. 162:5337–5344.[Abstract/Free Full Text]
  18. Shalom-Barak, T., J. Quach, and M. Lotz. 1998. Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J. Biol. Chem. 273:27467–27473.[Abstract/Free Full Text]
  19. Laan, M., J. Lotvall, K. F. Chung, and A. Linden. 2001. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br. J. Pharmacol. 133:200–206.[CrossRef][Medline]
  20. Nakae, S., Y. Komiyama, A. Nambu, K. Sudo, M. Iwase, I. Homma, K. Sekikawa, M. Asano, and Y. Iwakura. 2002. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17:375–387.[CrossRef][Medline]
  21. Schwarzenberger, P., W. Huang, P. Ye, P. Oliver, M. Manuel, Z. Zhang, G. Bagby, S. Nelson, and J. K. Kolls. 2000. Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis. J. Immunol. 164:4783–4789.[Abstract/Free Full Text]
  22. Quinton, L. J., S. Nelson, D. M. Boe, P. Zhang, Q. Zhong, J. K. Kolls, and G. J. Bagby. 2002. The granulocyte colony-stimulating factor response after intrapulmonary and systemic bacterial challenges. J. Infect. Dis. 185:1476–1482.[CrossRef][Medline]
  23. Fort, M. M., J. Cheung, D. Yen, J. Li, S. M. Zurawski, S. Lo, S. Menon, T. Clifford, B. Hunte, R. Lesley, T. Muchamuel, S. D. Hurst, G. Zurawski, M. W. Leach, D. M. Gorman, and D. M. Rennick. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–995.[CrossRef][Medline]
  24. Hurst, S. D., T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, J. K. Brieland, S. M. Zurawski, R. W. Chapman, G. Zurawski, and R. L. Coffman. 2002. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169:443–453.[Abstract/Free Full Text]
  25. Stockley, R. A. 2002. Neutrophils and the pathogenesis of COPD. Chest 121:151S–155S.[Free Full Text]
  26. Pettersen, C. A., and K. B. Adler. 2002. Airways inflammation and COPD: epithelial-neutrophil interactions. Chest 121:142S–150S.[Abstract/Free Full Text]
  27. Chmiel, J. F., M. Berger, and M. W. Konstan. 2002. The role of inflammation in the pathophysiology of CF lung disease. Clin. Rev. Allergy Immunol. 23:5–27.[CrossRef][Medline]



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