More recently, the IL-13 receptor was found on Th17 cells and was shown to regulate IL-17 production.46 The relationship of IL-17 and IL-13 in regulating mucus production during RSV exacerbated disease still remains to HDAC3 be established, but may demonstrate that the two cytokines play synergistic roles in mucus regulation. which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections. Nearly 98% of all infants become infected with respiratory syncytial virus (RSV) by the age of 2 years and experience severe bronchiolitis because their small airways easily become occluded.1 It is estimated by the U.S. Centers for Disease Control that up to 125, 000 pediatric hospitalizations in the United States each year are due to RSV. Amprolium HCl In addition, RSV is pathogenic for elderly patients and for those with chronic lung disease and asthma, and further is associated with a mortality rate of 30% to 100% in immunosuppressed individuals.2,3 RSV also is associated with acute exacerbations of chronic obstructive pulmonary disease, causing prolonged episodes of illness. Recurrent infections with RSV are common, and the pulmonary pathology is known to persist long after the virus has been cleared efficiently. RSV disease pathology is clinically characterized by airway hyperreactivity (AHR), increased mucus production, and inflammation.4C6 An altered immune environment due to an imbalance in the CD4 helper Th1 and Th2 responses is thought to underlie this disease phenotype. Recently it was reported that IL-17, produced by a subset of CD4 helper T cells (Th17 cells), was regulated by STAT-1 during RSV infections in rodents.7 The exact role of IL-17 in RSV disease pathogenicity is not known. Interleukin-17 belongs to a family of cytokines that has six members: IL-17 (also called IL-17A, the prototype) and IL-17B through IL-17F; IL-17E is also known as IL-25. IL-17F shares the strongest homology to IL-17.8,9 Both IL-17 and IL-17F are proinflammatory and have overlapping roles in the development of various autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. However, IL-17 plays a critical role in host defense during bacterial and fungal infection, whereas IL-17F is largely involved in the development of asthma and airway inflammation.9C11 Moreover. IL-17F does not up-regulate proinflammatory molecules to the same degree as does IL-17.12 The receptors for IL-17 and IL-17F are IL-17RA and IL-17RC, respectively; because these receptors have different tissue expression, the isoforms of IL-17 are tissue-specific. Expression of IL-17RC is limited to nonhematopoietic cells, but IL-17RA is expressed ubiquitously. IL-17 may promote Th2 responses in the lung through IL-17RA, whereas IL-17F has a regulatory role in limiting allergic Amprolium HCl asthma development.12C14 The combination of AHR and mucus production in the airways is a significant clinical outcome during viral infections. RSV infections induce significant AHR and mucus production in the airways of mice7,15,16 and induce Amprolium HCl neutrophilia in the lung epithelium.11,12,17 Although IL-17 has been reported to play a pathogenic role during the development of asthma by regulating mucin gene expression in the airways,11 its specific role in pathogenic responses during RSV infection is not known. Here, we report increased IL-17 production in infants with RSV infection and identify a role of IL-17 in a mouse model of primary RSV infection, as well as during viral exacerbation of allergic lung disease. Using either IL-17-deficient mice or neutralization of IL-17 significantly inhibited mucus production during RSV infection. In addition, blocking IL-17 significantly decreased viral load and altered cytotoxic CD8 T-cell marker expression. These responses were also observed in RSV-induced allergic airway exacerbation, suggesting that IL-17 plays an important role in the pathogenesis of RSV-induced disease. Materials and Methods Mice Female BALB/c mice, 6 to 8 8 weeks old, were purchased from the Jackson Laboratory (Bar Harbor, ME). The IL-17?/? mice, derived from breeder animals from the Jackson Laboratory, were a kind gift of Dr. Kathryn Eaton (University of Michigan).18 All mice were maintained in specific-pathogen-free facilities in the Unit for Laboratory Animal Medicine at the University of Michigan. The University Committee of Use and Care of Animals (UCUCA), University of Michigan, Ann Arbor, approved all animal experimental protocols, and experiments were conducted according to the guidelines provided by the UCUCA review committee. Human Specimens All human studies were performed in accordance with an approved University of Michigan institutional review board protocol after legal consent. The tracheal aspirate samples were diluted 50:50 with PBS containing complete anti-protease cocktail (Sigma-Aldrich, St. Louis, MO) and 0.5% Triton X-100 nonionic detergent to dissociate the mucus. Samples were aliquoted in 75 L and stored at ?80C until analysis. IL-17 was analyzed using a Bio-Plex 200 System (Bio-Rad Laboratories, Hercules, CA).
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