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Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor β

1997; Rockefeller University Press; Volume: 186; Issue: 9 Linguagem: Inglês

10.1084/jem.186.9.1567

1540-9538

Donald Y.M. Leung, Qutayba Hamid, Alessandra Vottero, Stanley J. Szefler, W Surs, Eleanor Minshall, George P. Chrousos, Dwight J. Klemm,

Immune Response and Inflammation

In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression. The molecular basis of GC insensitivity, however, is unknown. Alternative splicing of the GC receptor (R) pre-messenger RNA generates a second GCR, termed GCR-beta, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-alpha. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-beta-immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls. Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR. These abnormalities can be reproduced by transfection of cell lines with the GCR-beta gene resulting in significant reduction of their GCR-alpha DNA binding capacity. We conclude that increased expression of GCR-beta is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.