Peripheral blood CD4 but not CD8 t-lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy.
T-lymphocyte (T-LC)-derived cytokines have been implicated in asthma pathogenesis. Activation of peripheral blood CD4 but not CD8 T-LC and a Th2-type pattern of elevated cytokine mRNA expression in BAL fluid T-LC have been observed in asthmatics, but the principal source (CD4 or CD8 T-LC) of these cytokines is unknown. Our objective was to measure expression of Th1- and Th2-type cytokine mRNA and spontaneous secretion of IL-3, IL-5, and GM-CSF by peripheral blood CD4 and CD8 T-LC from asthmatics before and after oral glucocorticoid therapy and non-asthmatic controls. We used in situ hybridization to detect mRNA expression in isolated CD4 and CD8 T-LC, and an in vitro eosinophil survival assay to detect secretion of IL-3, IL-5, and GM-CSF in T-LC culture supernatants. Comparing the asthmatics with the controls, elevated percentages of CD4 T-LC expressed mRNA encoding IL-5, IL-4, and GM-CSF (P < 0.02) but not IL-3, IL-2, or IFN-gamma. In CD8 T-LC, mRNA expression was generally low with no significant differences between the groups. In the asthmatics, the percentages of CD4 T-LC expressing IL-5 mRNA correlated with disease severity and the numbers of peripheral blood eosinophils (P < 0.01). Culture supernatants of asthmatic CD4 but not CD8 T-LC exhibited significantly higher (P = 0.0003) eosinophil survival-prolonging activity compared with controls, in which low activity was detected. Inhibition with anti-cytokine antibodies suggested that GM-CSF, and to a lesser extent IL-5 and IL-3, could account for this activity. After oral glucocorticoid therapy of the asthmatics, lung function improved and the percentages of CD4 T-LC expressing mRNA encoding IL-3, IL-5, and GM-CSF but not IL-2, IL-4, or IFN-gamma were reduced (P < 0.04). Secretion of eosinophil survival-prolonging activity by the CD4 T-LC was also reduced (P = 0.004). We conclude that peripheral blood CD4 but not CD8 T-LC from asthmatics express cytokine mRNA in a Th2-type pattern and show elevated secretion of cytokines prolonging eosinophil survival. Glucocorticoid therapy of asthmatics is associated with a reduction in the percentages of CD4 T-LC expressing IL-3, IL-5, and GM-CSF mRNA and secretion of the corresponding proteins.
Corrigan
C J
CJ
Department of Allergy and Clinical Immunology, National Heart and Lung Institute, London, United Kingdom.
Hamid
Q
Q
North
J
J
Barkans
J
J
Moqbel
R
R
Durham
S
S
Gemou-Engesaeth
V
V
Kay
A B
AB
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology*; D014158:Transcription, Genetic
D016207:Cytokines; D005938:Glucocorticoids; D007377:Interleukin-3; D015848:Interleukin-5; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor