Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells.
BACKGROUND
Increased expression of IL-17F has been noted in the airway of asthmatic patients, but its role in asthma has not been fully elucidated. Insulin-like growth FACTOR-I (IGF-I) is known to be involved in airway remodelling and inflammation, while its regulatory mechanisms remain to be defined.


OBJECTIVE
To further clarify the biological function of IL-17F, we investigated whether IL-17F is able to regulate the expression of IGF-I in bronchial epithelial cells.


METHODS
Bronchial epithelial cells were stimulated with IL-17F in the presence or absence of T-helper type 2 cytokines. Various kinase inhibitors were added to the culture to identify the key signalling events leading to the expression of IGF-I, in conjunction with the use of short interfering RNAs (siRNAs) targeting mitogen- and stress-activated protein kinase (MSK) 1, p90 ribosomal S6 kinase (p90RSK), and cyclic AMP response element-binding protein (CREB).


RESULTS
IL-17F significantly induced IGF-I gene and protein expression, and co-stimulation with IL-4 and IL-13 augmented its production. MAP kinase kinase (MEK) inhibitors and the Raf1 kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Raf1 kinase inhibitor showed further inhibition. Overexpression of Raf1 and Ras dominant-negative mutants inhibited its expression. MSK1 inhibitors significantly blocked IL17F-induced IGF-I expression. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked its expression.


CONCLUSIONS
In bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB pathway in vitro.
Kawaguchi
M
M
Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. mkawaguchi@md.tsukuba.ac.jp
Fujita
J
J
Kokubu
F
F
Ohara
G
G
Huang
S-K
SK
Matsukura
S
S
Ishii
Y
Y
Adachi
M
M
Satoh
H
H
Hizawa
N
N
D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D015398:Signal Transduction
C440021:IL17F protein, human; D020381:Interleukin-17; D007334:Insulin-Like Growth Factor I