IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice.

Cystic fibrosis (CF) lung disease is characterized by an excessive inflammatory response associated with chronic Pseudomonas aeruginosa endobronchial infection. Compared with bronchoalveolar lavage fluid from healthy subjects, lavage fluid from patients with CF contains elevated proinflammatory cytokines but negligible amounts of the anti-inflammatory cytokine interleukin-10 (IL-10). We sought to determine whether IL-10 deficiency results in increased local and systemic morbidity in mice with chronic endobronchial infection with P. aeruginosa embedded in agar beads and to determine if exogenous IL-10 might reduce these effects. Infected IL-10 knockout mice had more severe weight loss (p = 0.04) and increased area of lung inflammation (28 +/- 4 versus 10 +/- 2%, p < 0.002) but no alterations in bacterial burden compared with wild-type mice. Infected CD-1 mice treated with IL-10 had improved survival (p = 0. 035), less severe weight loss (p < 0.005), fewer bronchoalveolar lavage neutrophils (3 x 10(5)/ml versus 5 x 10(6)/ml, p < 0.02), and decreased area of lung inflammation (11 +/- 2 versus 35 +/- 7%, p < 0.01) but no alterations in bacterial burden compared with placebo-treated mice. These data suggest that IL-10 is an important regulator of the inflammatory response to P. aeruginosa endobronchial infection and that further investigation into the use of IL-10 in CF is warranted.

[1]  A J Ratner,et al.  Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. , 1998, The Journal of clinical investigation.

[2]  S. Garg,et al.  Exogenous interleukin-10 fails to decrease the mortality or morbidity of sepsis. , 1998, Critical care medicine.

[3]  A. Pahl,et al.  Modulation of transcription factor NF‐κB by enantiomers of the nonsteroidal drug ibuprofen , 1998, British journal of pharmacology.

[4]  M. Hanes,et al.  Microbial Pathogenesis in Cystic Fibrosis: Pulmonary Clearance of Mucoid Pseudomonas aeruginosa and Inflammation in a Mouse Model of Repeated Respiratory Challenge , 1998, Infection and Immunity.

[5]  M. Konstan,et al.  Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. , 1997, The Journal of clinical investigation.

[6]  A. Lentsch,et al.  In vivo suppression of NF-kappa B and preservation of I kappa B alpha by interleukin-10 and interleukin-13. , 1997, The Journal of clinical investigation.

[7]  D. Corry,et al.  IL-10 improves lung injury and survival in Pseudomonas aeruginosa pneumonia. , 1997, Journal of immunology.

[8]  Melvin Berger,et al.  Current understanding of the inflammatory process in cystic fibrosis: Onset and etiology , 1997, Pediatric pulmonology.

[9]  T. Noah,et al.  Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. , 1997, The Journal of infectious diseases.

[10]  M. Kemna,et al.  Reduced IL‐10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR) , 1996, Clinical and experimental immunology.

[11]  M. Burdick,et al.  The Association between Mortality Rates and Decreased Concentrations of Interleukin-10 and Interleukin-1 Receptor Antagonist in the Lung Fluids of Patients with the Adult Respiratory Distress Syndrome , 1996, Annals of Internal Medicine.

[12]  S. Wenzel,et al.  Interleukin-10 regulation in normal subjects and patients with asthma. , 1996, Journal of Allergy and Clinical Immunology.

[13]  I. Siegler,et al.  Approaches to the nonparametric analysis of limited longitudinal data sets. , 1996, Experimental aging research.

[14]  M. Konstan,et al.  Inflammatory cytokines in cystic fibrosis lungs. , 1995, American journal of respiratory and critical care medicine.

[15]  M. Konstan,et al.  Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. , 1995, American journal of respiratory cell and molecular biology.

[16]  T. Standiford,et al.  Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. , 1995, Journal of immunology.

[17]  D. Leduc,et al.  Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. , 1995, The Journal of clinical investigation.

[18]  C. Morissette,et al.  Endobronchial inflammation following Pseudomonas aeruginosa infection in resistant and susceptible strains of mice , 1995, Infection and immunity.

[19]  Peng Wang,et al.  Interleukin (IL)-10 Inhibits Nuclear Factor B (NFB) Activation in Human Monocytes , 1995, The Journal of Biological Chemistry.

[20]  P. Ward,et al.  Regulatory effects of intrinsic IL-10 in IgG immune complex-induced lung injury. , 1995, Journal of immunology.

[21]  D. Riches,et al.  Early pulmonary inflammation in infants with cystic fibrosis. , 1995, American journal of respiratory and critical care medicine.

[22]  D. Schidlow,et al.  A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. , 1995, The Journal of pediatrics.

[23]  P. J. Byard,et al.  Effect of high-dose ibuprofen in patients with cystic fibrosis. , 1995, The New England journal of medicine.

[24]  J. Cidlowski,et al.  Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors , 1995, Molecular and cellular biology.

[25]  P. Ward,et al.  Protective effects of IL-4 and IL-10 against immune complex-induced lung injury. , 1993, Journal of immunology.

[26]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[27]  M. Konstan,et al.  Infection and inflammation of the lung in cystic fibrosis , 1993 .

[28]  T. Mosmann,et al.  IL-10 inhibits cytokine production by activated macrophages. , 1991, Journal of immunology.

[29]  M. Konstan,et al.  Ibuprofen attenuates the inflammatory response to Pseudomonas aeruginosa in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis. , 1990, The American review of respiratory disease.

[30]  C. Langston,et al.  A Mouse Model of Chronic Pulmonary Infection with Pseudomonas aeruginosa and Pseudomonas cepacia , 1987, Pediatric Research.

[31]  R. Crystal,et al.  Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. , 1986, Journal of applied physiology.

[32]  H. Colten,et al.  ALTERNATE-DAY PREDNISONE REDUCES MORBIDITY AND IMPROVES PULMONARY FUNCTION IN CYSTIC FIBROSIS , 1985, The Lancet.

[33]  R. A. Groeneveld,et al.  Practical Nonparametric Statistics (2nd ed). , 1981 .

[34]  J. A. Bass,et al.  A rat model of chronic respiratory infection with Pseudomonas aeruginosa. , 2015, The American review of respiratory disease.

[35]  Malay Ghosh,et al.  Nonparametric Methods in Longitudinal Studies , 1973 .

[36]  W. J. Conover,et al.  Practical Nonparametric Statistics , 1972 .

[37]  J. Gustafson,et al.  Cystic Fibrosis , 2009, Journal of the Iowa Medical Society.