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Club Cell Protein-16 Modifies Airway Inflammation in an IL-13 Model of Induced Airway Responses
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A1301 - Club Cell Protein-16 Modifies Airway Inflammation in an IL-13 Model of Induced Airway Responses
Author Block: J. Gozdz1, D. Francisco2, A. Manne2, K. J. Addison2, F. D. Martinez3, J. G. Ledford1, S. Guerra2, M. Kraft4; 1Medicine, University of Arizona, Tucson, AZ, United States, 2University of Arizona, Tucson, AZ, United States, 3Univ of Arizona, Tucson, AZ, United States, 4Dept of Medicine, Univ of Arizona Health Sciences Ctr, Tucson, AZ, United States.
Rationale: Club cell secretory protein-16 (CC16), a member of the secretoglobin family of proteins, is abundant in normal airways. It has been shown to play a role in anti-inflammatory and anti-oxidant responses within lung. Despite the described association between CC16 and asthma, the mechanism of its action has not been elucidated. Previous studies conducted by our group demonstrated that mice lacking CC16 had a significantly increased baseline airway resistance. To gain a better understanding of the role of CC16 in lung inflammation we examined responses to the type 2 cytokine IL-13, in wild type and CC16 deficient mice and in airway epithelial cells in patients with and without asthma.
Methods: Primary human lung epithelial cell cultures from asthmatic and non-asthmatic participants obtained by bronchoscopy were exposed to IL-13 with and without exposure to recombinant CC16 (20 ng/ml) for 48 hours. Expression of MUC5AC and CLCA1 was determined via qPCR. Recombinant IL-13 (500 ng) was administered intranasaly to mice sufficient (WT) and deficient (CC16-/-) in CC16 every 24 hours for a total of 3 administrations. Airway inflammation was assessed 24 hours after the last administration. BAL was evaluated for differential cell counts. Eotaxin, keratinocyte chemoattractant (KC) and interleukin-6 (IL-6) were measured in BAL by ELISA.
Results: Cells from asthmatics and non-asthmatic participants showed similar upregulation of MUC5AC in response to IL-13, treatment with CC16 resulted in a trend towards decreased expression in asthmatic participants only. Exposure to CC16 resulted in a trend towards a decreased expression of CLCA1 in cells from non-asthmatic participants. Mice deficient in CC16 demonstrated significantly increased BAL eosinophilia in response to IL-13 compared to WT that was independent of eotaxin. Total macrophages were decreased in both WT and CC16-/- mice after IL-13 treatment. Treatment with IL-13 lead to increased KC levels in WT mice but not in animals deficient for CC16. No differences were detected for IL-6 in response to IL-13.
Conclusion: Lack of CC16 results in modified inflammatory responses in both human primary cell culture and mouse model. Mice deficient for CC16 displayed eosinophilic inflammatory response to IL-13 treatment, in agreement with the association between lower levels of serum CC16 and increased likelihood of asthma. Eotaxin and KC levels in BAL suggest that absence of CC16 modifies immune responses in the lungs in a complex manner rather than simply reducing airway inflammation.
Author Block: J. Gozdz1, D. Francisco2, A. Manne2, K. J. Addison2, F. D. Martinez3, J. G. Ledford1, S. Guerra2, M. Kraft4; 1Medicine, University of Arizona, Tucson, AZ, United States, 2University of Arizona, Tucson, AZ, United States, 3Univ of Arizona, Tucson, AZ, United States, 4Dept of Medicine, Univ of Arizona Health Sciences Ctr, Tucson, AZ, United States.
Rationale: Club cell secretory protein-16 (CC16), a member of the secretoglobin family of proteins, is abundant in normal airways. It has been shown to play a role in anti-inflammatory and anti-oxidant responses within lung. Despite the described association between CC16 and asthma, the mechanism of its action has not been elucidated. Previous studies conducted by our group demonstrated that mice lacking CC16 had a significantly increased baseline airway resistance. To gain a better understanding of the role of CC16 in lung inflammation we examined responses to the type 2 cytokine IL-13, in wild type and CC16 deficient mice and in airway epithelial cells in patients with and without asthma.
Methods: Primary human lung epithelial cell cultures from asthmatic and non-asthmatic participants obtained by bronchoscopy were exposed to IL-13 with and without exposure to recombinant CC16 (20 ng/ml) for 48 hours. Expression of MUC5AC and CLCA1 was determined via qPCR. Recombinant IL-13 (500 ng) was administered intranasaly to mice sufficient (WT) and deficient (CC16-/-) in CC16 every 24 hours for a total of 3 administrations. Airway inflammation was assessed 24 hours after the last administration. BAL was evaluated for differential cell counts. Eotaxin, keratinocyte chemoattractant (KC) and interleukin-6 (IL-6) were measured in BAL by ELISA.
Results: Cells from asthmatics and non-asthmatic participants showed similar upregulation of MUC5AC in response to IL-13, treatment with CC16 resulted in a trend towards decreased expression in asthmatic participants only. Exposure to CC16 resulted in a trend towards a decreased expression of CLCA1 in cells from non-asthmatic participants. Mice deficient in CC16 demonstrated significantly increased BAL eosinophilia in response to IL-13 compared to WT that was independent of eotaxin. Total macrophages were decreased in both WT and CC16-/- mice after IL-13 treatment. Treatment with IL-13 lead to increased KC levels in WT mice but not in animals deficient for CC16. No differences were detected for IL-6 in response to IL-13.
Conclusion: Lack of CC16 results in modified inflammatory responses in both human primary cell culture and mouse model. Mice deficient for CC16 displayed eosinophilic inflammatory response to IL-13 treatment, in agreement with the association between lower levels of serum CC16 and increased likelihood of asthma. Eotaxin and KC levels in BAL suggest that absence of CC16 modifies immune responses in the lungs in a complex manner rather than simply reducing airway inflammation.
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