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The human antimicrobial peptide cathelicidin acts as effector molecule of
the innate immune system with direct antimicrobial and immunomodulatory
functions. The aim of this study was to test whether the cathelicidin LL-37
modulates the response of neutrophils to microbial stimulation. Furthermore
we wanted to investigate whether the presence of cathelicidin reduces pulmonary
emphysema and enhances of pulmonary epithelial repair after acute
lung injury induced by naphthalene.
Human neutrophils were stimulated with LPS, Staphylococcus aureus and
Pseudomonas aeruginosa following incubation with LL-37. Cytokine release
was measured by ELISA. Reactive Oxygen Species (ROS) production of neutrophils
was determined by luminometric and a flow cytometric methods.
Peritoneal mouse neutrophils isolated from CRAMP deficient and wildtype
animals were treated with LPS and TNF-a was measured in the supernatant
by ELISA. Antimicrobial activity of neutrophils was detected by incubating
neutrophils isolated from CRAMP knockout and wildtype mice with bacteria.
Pulmonary emphysema was induced in mice by intratracheal instillation
of elastase and induction of emphysema was evaluated depending on morphological
parameter like mean linear intercept (Lm).
To test whether cathelicidin enhances lung tissue repair, a selective injury
was induced to mouse nonciliated bronchiolar epithelial cells (clara) with
naphthalene. The repair of clara cells were determined by immunohistochemical
staining for CC10 protein. Incubation with LL-37 significantly decreased
the release of proinflammatory cytokines from human neutrophils stimulated
with TLR ligands or whole bacteria. LL-37 induced the production of ROS
and the increased engulfment of bacteria into neutrophils. Neutrophils from
CRAMP deficient mice released significantly more TNF-a after LPS stimulation
and showed decreased antimicrobial activity as compared to cells from
Absence of cathelicidin in CRAMP deficient mice decreases significantly
the repair of airway epithelium and increases the induction of pulmonary
emphysema-induced by application of elastase. In conclusion, LL-37 modulates
the response of various innate immune mechanisms involved in tissue
homeostasis and inflammation. Cathelicidin controls the release of inflammatory
mediators while increasing neutrophils antimicrobial activity.