IL-1 beta stimulates divergent upper and lower airway epithelial cell CCL5 secretion.
Direct infection of respiratory epithelium induces chemokine secretion and upregulates cytokine networks, which are central in regulating inflammation. IL-1beta may have a pivotal role in such networks. Differential control of chemokine secretion within specific airway regions, which have distinct roles in immunity, is not well characterized. We investigated IL-1beta-induced CXCL8 and CCL5 secretion from primary normal human bronchial and small airway epithelial cells, and the alveolar cell line A549. CXCL8 was secreted by all cells, but only lower airway cells secreted CCL5. IL-1beta induced nuclear translocation of NF-kappaB (p50, p65 and c-Rel subunits), NF-IL-6 and AP-1, each with distinct kinetics. This was associated with high level CCL5 promoter activation, via transcription factor binding to multiple regions, including NF-kappaB, AP-1 and NF-IL-6 sites. The IL-1-related cytokine IL-18 did not drive or modulate IL-1beta-induced CXCL8 or CCL5 secretion. In summary, IL-1beta, but not IL-18, induces transcription-dependent lower airway epithelial cell-specific CCL5 secretion. Differential chemokine secretion may have profound effects on local leukocyte influx within upper or lower airways exposed to airway infection or environmental stimuli, which might then require different anti-inflammatory strategies.
Thomas
Lynette H
LH
Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College (Hammersmith Campus), Du Cane Road, London, W12 0NN, UK.
Wickremasinghe
Melissa I Y
MI
Friedland
Jon S
JS
D002460:Cell Line; D045744:Cell Line, Tumor; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D053583:Interleukin-1beta; D016209:Interleukin-8