In vivo expression of signal transducer and activator of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic rhinitis: effect of topical corticosteroids.
BACKGROUND
The allergen-induced late nasal response is associated with a high local expression of interleukin (IL) -4, a TH2-type cytokine implicated in immunoglobulin (Ig) E production, tissue eosinophilia and other events considered to be relevant to allergic inflammation. Interaction of IL-4 with its receptor activates at least two distinct signalling pathways that culminate in the transcription of specific target genes. One pathway involves the activation of a transcription factor termed signal transducer and activator of transcription factor 6 (STAT6).


OBJECTIVE
To investigate the expression of STAT6 in the allergen-induced late nasal response and to examine the effect of local steroid treatment on STAT6 expression.


METHODS
Inferior turbinate biopsies were obtained from subjects with allergic rhinitis out of the allergen season. Subjects were then randomized into topical steroid- (n = 6) and placebo-treated (n = 6) groups in a double-blind fashion. After a 6-week treatment period, a second nasal biopsy was performed 24 h after local challenge with allergen. STAT6 immunoreactivity was examined in biopsy specimens by immunocytochemistry using a specific monoclonal antibody. Numbers of inflammatory cells (CD3+ T cells and MBP+ eosinophils) and IL-4 mRNA+ cells were investigated by immunocytochemistry and in situ hybridization, respectively.


RESULTS
STAT6 immunoreactivity was detected in all biopsies studied and localized predominantly to inflammatory tissue of the nasal mucosa. After allergen challenge, expression of STAT6 was markedly increased in placebo-treated patients (P < 0.01). By confocal microscopy, STAT6 was localized to the cytoplasm and the nucleus of positively-staining cells. The allergen-induced increase in STAT6 immunoreactive cells was not observed in the steroid-treated patients. The change in STAT6 immunoreactivity after allergen challenge correlated significantly with the change in numbers IL-4 mRNA+ cells (r = 0.74, P = 0.006) and CD3+ T cells (r = 0.76, P = 0. 004), but not MBP+ eosinophils.


CONCLUSIONS
This study provides the first evidence of increased STAT6 expression in vivo in human allergic inflammation. The results support a role for STAT6 and IL-4 in the pathogenesis of late nasal response and show that decreases in STAT6 expression parallel the reduction in IL-4 expression that occurs with topical steroid treatment.
Ghaffar
O
O
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Christodoulopoulos
P
P
Lamkhioued
B
B
Wright
E
E
Ihaku
D
D
Nakamura
Y
Y
Frenkiel
S
S
Hamid
Q
Q
D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001798:Blood Proteins / Q000096:biosynthesis; D001993:Bronchodilator Agents / Q000008:administration & dosage; D017252:CD3 Complex / Q000096:biosynthesis; D004311:Double-Blind Method; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D018655:Lymphocyte Count; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D012260:Ribonucleases; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013256:Steroids; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000276:immunology
D000485:Allergens; D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D001993:Bronchodilator Agents; D017252:CD3 Complex; D047091:Eosinophil Granule Proteins; D005938:Glucocorticoids; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D013256:Steroids; D015534:Trans-Activators; D015847:Interleukin-4; D012260:Ribonucleases