STAT4 activation in smokers and patients with chronic obstructive pulmonary disease.
Activation of the transcription factor signal transducer and activator of transcription (STAT)-4 is critical for the differentiation of T-helper 1 cells/type-1 cytotoxic T-cells and the production of interferon (IFN)-gamma. Expression of STAT4, phospho-STAT4, IFN-gamma and T-box expressed in T-cells (T-bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)-derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59 +/- 16% predicted), 14 smokers with normal lung function (FEV1 106 +/- 12% pred) and 12 nonsmoking subjects (FEV1 111 +/- 14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho-STAT4+ cells was increased (240 (22-406) versus 125 (0-492) versus 29 (0-511) cells mm(-2)) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho-STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN-gamma+ cells. Similar results were seen in BAL (2.8 (0.2-5.9) versus 1.03 (0.09-1.6) versus 0.69 (0-2.3) lymphocytes x mL(-1) x 10(3)). In all smokers who underwent lavage, phospho-STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNgamma+ lymphocytes. T-bet expression was not altered in bronchial biopsies and BAL-derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T-helper 1 cell/type-1 cytotoxic T-cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.
Salvatore Maugeri Foundation, IRCCS, Medical Centre of Rehabilitation, Division of Pulmonary Disease, Veruno, Italy.
A
A
Di Stefano
G
G
Caramori
A
A
Capelli
I
I
Gnemmi
F L
FL
Ricciardolo
T
T
Oates
C F
CF
Donner
K F
KF
Chung
P J
PJ
Barnes
I M
IM
Adcock
D000368:Aged; D001707:Biopsy, Needle; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001999:Bronchoscopy / Q000379:methods; D016022:Case-Control Studies; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology*; D012016:Reference Values; D012129:Respiratory Function Tests; D018570:Risk Assessment; D050797:STAT4 Transcription Factor; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D012907:Smoking / Q000276:immunology / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators