Interleukin- (IL-) 17 is important in the development of asthma and host defense against pneumococci. We determined the role of IL-17 in the risk of pneumococcal pneumonia. We challenged mice intranasally with a bioluminescent Streptococcus pneumoniae strain after sensitization and challenge with ovalbumin (OVA). We measured the levels of cytokines, including IL-17 (pg/mL), in the lung homogenate in experimental mice with and without OVA sensitization/challenge, as well as those with and without pneumococcal pneumonia. IL-17 levels were significantly lower in OVA-sensitized/challenged mice (9.69 1.49), compared to the control mice (20.92 1.82, < 0.001). In our overall analysis, including IL-4 and IL-17 levels and OVA sensitization/challenge, IL-4 levels (OR: 81.9, 95%CI: 4.3–1523 per increment of 1.0？pg/mL, = 0.003) were more significant than IL-17 levels (OR: 1.1, 95%CI: 1.03–1.17 per increment of 1.0？pg/mL, = 0.003) in determining the risk of pneumococcal pneumonia. IL-17 levels result in a much smaller impact on the risk for pneumococcal pneumonia, compared to IL-4 levels. 1. Introduction Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis and has caused substantial morbidity and mortality in the United States and worldwide, especially in young children. Recent estimates of childhood deaths caused by Streptococcus pneumoniae range from 70,000 to 1 million every year worldwide, and S. pneumoniae caused around 11% of all deaths in children aged 1–59 months [1]. In 2000, about 14.5 million episodes of serious pneumococcal disease were estimated to occur, and pneumococcal disease caused about 826,000 deaths in children aged 1–59 months [1]. In the US, 40,000 cases of fatal pneumococcal infections per year have been reported [2]. Recently some studies reported that individuals with asthma have a significantly increased risk of invasive pneumococcal disease, compared to those without asthma [3, 4]. Thus, the Advisory Committee on Immunization Practices has a recommendation for the use of 23-valent pneumococcal polysaccharide vaccine (PPV23) for the prevention of invasive pneumococcal disease in asthmatics [5]. At present, little is known about the mechanisms underlying the increased risk of invasive pneumococcal disease among individuals with asthma. We previously reported that a T-helper 2 (Th2) predominant immune response (e.g., IL-4) to OVA sensitization was a significant risk factor for pneumococcal infection, whereas allergic sensitization itself was protective against pneumococcal pneumonia [6]. Others also
References
[1]
K. L. O'Brien, L. J. Wolfson, J. P. Watt et al., “Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates,” The Lancet, vol. 374, no. 9693, pp. 893–902, 2009.
[2]
D. Bogaert, M. N. Engelen, A. J. M. Timmers-Reker et al., “Pneumococcal carriage in children in The Netherlands: a molecular epidemiological study,” Journal of Clinical Microbiology, vol. 39, no. 9, pp. 3316–3320, 2001.
[3]
T. R. Talbot, T. V. Hartert, E. Mitchel et al., “Asthma as a risk factor for invasive pneumococcal disease,” New England Journal of Medicine, vol. 352, no. 20, pp. 2082–2090, 2005.
[4]
Y. J. Juhn, H. Kita, B. P. Yawn et al., “Increased risk of serious pneumococcal disease in patients with asthma,” Journal of Allergy and Clinical Immunology, vol. 122, no. 4, pp. 719–723, 2008.
[5]
The Advisory Committee on Immunization Practices, “ACIP provisional recommendations foruse of pneumococcal vaccines,” 2008, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5934a3.htm.
[6]
C. I. Kang, M. S. Rouse, R. Patel, H. Kita, and Y. J. Juhn, “Allergic airway inflammation and susceptibility to pneumococcal pneumonia in a murine model with real-time in vivo evaluation,” Clinical and Experimental Immunology, vol. 156, no. 3, pp. 552–561, 2009.
[7]
C. Moser, H. K. Johansen, Z. Song, H. P. Hougen, J. Rygaard, and N. H？iby, “Chronic Pseudomonas aeruginosa lung infection is more severe in Th2 responding BALB/c mice compared to Th1 responding C3H/HeN mice,” APMIS, vol. 105, no. 11, pp. 838–842, 1997.
[8]
M. Kawaguchi, M. Adachi, N. Oda, F. Kokubu, and S. K. Huang, “IL-17 cytokine family,” Journal of Allergy and Clinical Immunology, vol. 114, no. 6, pp. 1265–1273, 2004.
[9]
R. H. Wilson, G. S. Whitehead, H. Nakano, M. E. Free, J. K. Kolls, and D. N. Cook, “Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 8, Article ID 200904, pp. 720–730, 2009.
[10]
S. Schnyder-Candrian, D. Togbe, I. Couillin et al., “Interleukin-17 is a negative regulator of established allergic asthma,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2715–2725, 2006.
[11]
Z. Zhang, T. B. Clarke, and J. N. Weiser, “Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice,” Journal of Clinical Investigation, vol. 119, no. 7, pp. 1899–1909, 2009.
[12]
Y. J. Lu, J. Gross, D. Bogaert et al., “Interleukin-17A mediates acquired immunity to pneumococcal colonization,” PLoS Pathogens, vol. 4, no. 9, Article ID e1000159, 2008.
[13]
H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005.
[14]
H. Hoshino, M. Laan, M. Sj？strand, J. L？tvall, B. E. Skoogh, and A. Lindén, “Increased elastase and myeloperoxidase activity associated with neutrophil recruitment by IL-17 in airways in vivo,” Journal of Allergy and Clinical Immunology, vol. 105, no. 1 I, pp. 143–149, 2000.
[15]
K. P. Francis, J. Yu, C. Bellinger-Kawahara et al., “Visualizing pneumococcal infections in the lungs of live mice using bioluminescent Streptococcus pneumoniae transformed with a novel gram-positive lux transposon,” Infection and Immunity, vol. 69, no. 5, pp. 3350–3358, 2001.
[16]
S. Z. Ben-Sasson, J. Hu-Li, J. Quiel et al., “IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 17, pp. 7119–7124, 2009.
[17]
Y. Chung, S. H. Chang, G. J. Martinez et al., “Critical regulation of early Th17 cell differentiation by Interleukin-1 signaling,” Immunity, vol. 30, no. 4, pp. 576–587, 2009.
[18]
L. Lyakh, G. Trinchieri, L. Provezza, G. Carra, and F. Gerosa, “Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans,” Immunological Reviews, vol. 226, no. 1, pp. 112–131, 2008.
[19]
S. C. Liang, X. Y. Tan, D. P. Luxenberg et al., “Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides,” Journal of Experimental Medicine, vol. 203, no. 10, pp. 2271–2279, 2006.
[20]
G. Matsuzaki and M. Umemura, “Interleukin-17 as an effector molecule of innate and acquired immunity against infections,” Microbiology and Immunology, vol. 51, no. 12, pp. 1139–1147, 2007.
[21]
Z. Jaffar, M. E. Ferrini, L. A. Herritt, and K. Roberts, “Cutting edge: lung mucosal Th17-mediated responses induce polymeric Ig receptor expression by the airway epithelium and elevate secretory IgA levels,” Journal of Immunology, vol. 182, no. 8, pp. 4507–4511, 2009.
[22]
C. S. Kaetzel, “The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces,” Immunological Reviews, vol. 206, pp. 83–99, 2005.
[23]
R. Luo, B. Mann, W. S. Lewis et al., “Solution structure of choline binding protein A, the major adhesin of Streptococcus pneumoniae,” EMBO Journal, vol. 24, no. 1, pp. 34–43, 2005.
[24]
Y. Iwakura, S. Nakae, S. Saijo, and H. Ishigame, “The roles of IL-17A in inflammatory immune responses and host defense against pathogens,” Immunological Reviews, vol. 226, no. 1, pp. 57–79, 2008.
[25]
M. I. Koenders, L. A. B. Joosten, and W. B. Van Den Berg, “Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis,” Annals of the Rheumatic Diseases, vol. 65, supplement 3, pp. iii29–iii33, 2006.
[26]
L. A. Tesmer, S. K. Lundy, S. Sarkar, and D. A. Fox, “Th17 cells in human disease,” Immunological Reviews, vol. 223, no. 1, pp. 87–113, 2008.
[27]
T. Zelante, A. De Luca, P. Bonifazi et al., “IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance,” European Journal of Immunology, vol. 37, no. 10, pp. 2695–2706, 2007.
[28]
C. Beisswenger, K. Kandler, C. Hess et al., “Allergic airway inflammation inhibits pulmonary antibacterial host defense,” Journal of Immunology, vol. 177, no. 3, pp. 1833–1837, 2006.
[29]
A. Q. Khan, Y. Shen, Z. Q. Wu, T. A. Wynn, and C. M. Snapper, “Endogenous pro- and anti-inflammatory cytokines differentially regulate an in vivo humoral response to Streptococcus pneumoniae,” Infection and Immunity, vol. 70, no. 2, pp. 749–761, 2002.
