Neutrophil defensins stimulate the release of cytokines by airway epithelial cells: modulation by dexamethasone.
OBJECTIVE
Neutrophils may contribute to recruiting other cells to sites of inflammation by generating chemotactic signals themselves, or by stimulating other cell types to release chemoattractants such as interleukin-8 (IL-8). Recently, we demonstrated that neutrophil-derived alpha-defensins are able to increase IL-8 expression in airway epithelial cells. In addition, it has previously been reported that neutrophil elastase-induced IL-8 synthesis was insensitive to inhibition by the glucocorticoid dexamethasone. The aim of the present study was to investigate the effect of defensins on the expression of various cytokines in cultured airway epithelial cells and to examine the effect of dexamethasone on defensin-induced cytokine synthesis in these cells.


METHODS
Cultures of A549 cells and primary bronchial epithelial cells (PBEC) were stimulated with defensins either alone or in the presence of dexamethasone. Supernatants were analyzed for IL-8, ENA-78, IL-6, MCP-1 and GM-CSF by ELISA. In addition, IL-8 and ENA-78 mRNA was detected by Northern blot analysis.


RESULTS
Defensins increased IL-8 expression, ENA-78, MCP-1 and GM-CSF release from A549 cells, whereas in PBEC only IL-8 and IL-6 were increased. Pre-treatment with dexamethasone significantly reduced defensin-induced IL-6, IL-8 and ENA-78 synthesis in airway epithelial cells. In addition, dexamethasone also reduced the neutrophil chemotactic activity in supernatants of these cells.


CONCLUSIONS
The results from the present study indicate that defensins differentially induce cytokine secretion by A549 cells and PBEC. Glucocorticoids may interfere with the defensin-induced inflammatory process by reducing defensin-induced cytokine secretion in lung epithelial cells.
van Wetering
S
S
Department of Pulmonology, Leiden University Medical Center, The Netherlands.
Mannesse-Lazeroms
S P G
SP
van Sterkenburg
M A J A
MA
Hiemstra
P S
PS
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D023082:Defensins / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D009504:Neutrophils / Q000276:immunology*
D000890:Anti-Infective Agents; C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D023082:Defensins; D016209:Interleukin-8; D003907:Dexamethasone