Role of IL-10 deficiency in excessive nuclear factor-kappaB activation and lung inflammation in cystic fibrosis transmembrane conductance regulator knockout mice

Aicha Saadane, Jindrich Soltys, Melvin Berger
Journal of Allergy and Clinical Immunology 2005, 115 (2): 405-11

BACKGROUND: Patients with cystic fibrosis (CF) and CF transmembrane conductance regulator knockout (CF-KO) mice are deficient in pulmonary IL-10 and have excessive inflammatory response to Pseudomonas aeruginosa infection.

OBJECTIVE: We hypothesized that local IL-10 deficiency in the lung was responsible for prolonged and excessive inflammatory responses and observations of inflammation in the absence of infection.

METHODS: To determine whether IL-10 deficiency could account for persistent inflammation in CF mice independent of interactions of bacteria with epithelial cells, we challenged IL-10-knockout (IL-10-KO), CF-KO, and wild-type (WT) mice intratracheally with LPS and determined the effects of IL-10 replacement in CF-KO mice.

RESULTS: In response to LPS, IL-10-KO and CF-KO mice had more neutrophils and proinflammatory cytokines in bronchoalveolar lavage than WT mice. Both types of knockout mice had more profound and prolonged consumption of I-kappaB and increased activation of nuclear factor kappaB (NF-kappaB). Activated NF-kappaB persisted for 6 to 8 hours in CF-KO and IL-10-KO mice but was not detected beyond 2 hours in WT mice. IL-10 treatment of CF-KO mice attenuated the reduction in I-kappaBalpha and activation of NF-kappaB and reduced the excessive inflammation.

CONCLUSION: Similarities in the responses of CF-KO and IL-10-KO mice and correction of excessive responses in CF mice by exogenous IL-10 suggest that deficiency of IL-10 may be responsible for prolonged and excessive inflammatory responses in CF. Because LPS was used as the stimulus, these excessive responses are independent of any possible differences in the interactions of bacteria with CF epithelial cells.

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