Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma.
BACKGROUND
IL-17A and IL-19 are highly expressed in chronic inflammatory diseases, such as psoriasis and asthma. IL-19 plays a significant role in the enhancement of T(H)2 cytokine secretion in allergic diseases, but its cellular source in asthmatic patients remains unknown.


OBJECTIVE
Our aims were to determine whether the epithelium is a major source of airway mucosal IL-19 and to elucidate the mechanism of gene expression regulation.


METHODS
Immunofluorescent staining was used to determine IL-19 protein expression in tracheal tissue sections of various airway diseases. Well-differentiated primary human bronchial epithelial cultures and a corresponding cell line were used as in vitro models to study gene regulation.


RESULTS
We found significantly higher IL-19 expression in airway epithelia of asthmatic patients than in epithelia of patients with other diseases. Using a cytokine panel, we demonstrated the upregulation of IL-19 expression in cultures by two T(H)2 cytokines, IL-4 and IL-13, in addition to the previously found T(H)17 cytokine IL-17A. Moreover, cotreatment of IL-17A and IL-4/IL-13 synergistically upregulated IL-19 expression. Using siRNA and chemical inhibitor approaches, we demonstrated a transcriptional regulation of IL-19 by nuclear factor kappaB and signal transducer and activator of transcription (STAT) 6. The addition of IL-13 to IL-17A stimulation triggers a shift from nuclear factor kappaB-dependent transcriptional regulation to one that is STAT6 based. Using chromatin immunoprecipitation assays, we demonstrated the presence of STAT6-binding elements in the IL-19 promoter region.


CONCLUSIONS
We propose that an IL-17A- and IL-13-induced synergism in IL-19 stimulation in airway epithelia occurs through a STAT6-dependent pathway.
Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Davis, Calif 95616, USA. feihuang@ucdavis.edu
Fei
F
Huang
Shinichiro
S
Wachi
Philip
P
Thai
Artem
A
Loukoianov
Kin Hup
KH
Tan
Rosanna Malbran
RM
Forteza
Reen
R
Wu
D001249:Asthma / Q000378:metabolism*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018793:Interleukin-13 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000378:metabolism
C421250:IL19 protein, human; D018793:Interleukin-13; D020381:Interleukin-17; D007378:Interleukins; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4