Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium.
BACKGROUND
Asthma is associated with increased production of IL-4 and IL-13.


OBJECTIVE
Because many of the effects of these cytokines are mediated by activation of signal transducer and activator of transcription 6 (STAT-6), we investigated expression and function of this transcription factor in the airways.


METHODS
STAT-6 expression was investigated through use of immunohistochemistry or RT-PCR applied to bronchial biopsy specimens or brushings from normal control or asthmatic subjects. STAT-6 function was investigated by means of Western blotting and ELISA applied to primary epithelial cell cultures.


RESULTS
Immunohistochemistry revealed that the bronchial epithelium was the major site of STAT-6 expression, both cytoplasmic and nuclear staining being observed. The level of STAT-6 expression in subjects with mild asthma (median [range] percent epithelial staining, 3.4% [0% to 16.0%]; n = 14) did not differ significantly from that in normal controls (4.7% [0.0% to 20.0%]; n = 11); however, in subjects with severe asthma, epithelial STAT-6 expression (13.7% [4.8% to 25.7%]; n = 9) was increased in comparison with subjects with mild asthma and normal controls (P < .05). RT-PCR analysis showed that epithelial STAT-6 expression was heterogeneous and comprised both full-length STAT-6 and the dominant-negative variant that lacks the SH2 domain. Treatment of primary cultures of bronchial epithelial cells with IL-4 resulted in STAT-6 phosphorylation and stimulation of IL-8 secretion; however, no difference in the responses of epithelial cells was observed between normal (n = 12) and asthmatic (n = 14) donors.


CONCLUSIONS
These data demonstrate expression and activation of STAT-6 in normal and asthmatic bronchial epithelium. The activity of this transcription factor is likely to play a key role in mediating the responses of the bronchial epithelium to T(H)2 cytokines that are characteristic of the asthmatic phenotype.
Mullings
R E
RE
Division of Respiratory Cell and Molecular Biology, School of Medicine, Southampton General Hospital, United Kingdom.
Wilson
S J
SJ
Puddicombe
S M
SM
Lordan
J L
JL
Bucchieri
F
F
Djukanović
R
R
Howarth
P H
PH
Harper
S
S
Holgate
S T
ST
Davies
D E
DE
D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000166:cytology*; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D053613:Janus Kinase 1; D008954:Models, Biological; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D018793:Interleukin-13; D016209:Interleukin-8; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1