Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma.
BACKGROUND
Glucocorticoids are the mainstay of asthma therapy; however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function.


OBJECTIVE
To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function.


METHODS
Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured.


RESULTS
Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1.


CONCLUSIONS
These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma.


CONCLUSIONS
Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.
Vasavda
Nisha
N
Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
Eichholtz
Thomas
T
Takahashi
Atsushi
A
Affleck
Karen
K
Matthews
John G
JG
Barnes
Peter J
PJ
Adcock
Ian M
IM
D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000096:biosynthesis* / Q000235:genetics*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
D051338:Cofilin 1; D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003907:Dexamethasone