Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells.
Lung epithelial cells contribute to local inflammation by the production of pro-inflammatory mediators like interleukin (IL)-8 and IL-6. Although their production depends on gene transcription, previous studies showed that post-transcriptional mechanisms modulate IL-8 and IL-6 production. Human lung epithelial cells turn from normoresponsive into hyperresponsive IL-8- and IL-6-producing cells when their IL-8 and IL-6 mRNA degradation is reduced. We hypothesized that IL-17, a mediator predominantly released by memory T cells and present in airways of individuals with asthma, would modulate rather than induce IL-8 and IL-6 production by both human lung epithelial cells and fibroblasts. We show here for both cell types that IL-17 was a weak stimulus of IL-8 and IL-6 production, but markedly enhanced IL-8 and IL-6 responses to another stimulus, such as tumor necrosis factor-alpha. This modulatory effect of IL-17 was paralleled by a reduced IL-8 and IL-6 mRNA degradation, with no effect on IL-8 and IL-6 gene transcription. In conclusion, IL-17 particularly affects post-transcriptional regulation of IL-8 and IL-6 expression leading to enhanced IL-8 and IL-6 responses to secondary stimuli, and is only a weak proinflammatory stimulus by itself. This poses the interesting concept that by releasing IL-17 from memory T cells, the adaptive immune system instructs lung structural cells as part of the innate immune system to respond more vigorously.
van den Berg
Arjen
A
Department of Pulmonology and Laboratory of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands. a.vandenberg@amc.uva.nl
Kuiper
Mathys
M
Snoek
Mieke
M
Timens
Wim
W
Postma
Dirkje S
DS
Jansen
Henk M
HM
Lutter
René
R
D001249:Asthma / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D012130:Respiratory Hypersensitivity; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015500:Chloramphenicol O-Acetyltransferase