Vol. 284, Issue 6, C1429-C1437, June 2003
Robust induction of PGHS-2 by IL-1 in orbital fibroblasts
results from low levels of IL-1 receptor antagonist expression
H. James
Cao1,
Rui
Han1,2,3, and
Terry J.
Smith1,2,3,4
1 Division of Molecular and Cellular Medicine,
Department of Medicine, Department of Biochemistry and Molecular
Biology, Albany Medical College, Samuel S. Stratton Veterans Affairs
Medical Center, Albany, New York 12208; 2 Division
of Molecular Medicine, Harbor-UCLA Medical Center, Los Angeles
90502; 3 David Geffen School of Medicine, University of
California, Los Angeles 90095; and 4 Veterans
Affairs Medical Center, Long Beach, California 90822
Human orbital
fibroblasts are more susceptible to some actions of proinflammatory
cytokines than are fibroblasts from other anatomic regions. These cells
produce high levels of PGE2 when activated by cytokines.
Here we report that they express high levels of
prostaglandin-endoperoxide H synthase (PGHS)-2, the inflammatory
cyclooxygenase, when treated with IL-1
. This induction results from
enhanced PGHS-2 mRNA stability and small increases in gene promoter
activity. The enhanced transcript stability is a result of actions of
the cytokine on the 3'-untranslated region. Orbital fibroblasts, unlike
those from skin, fail to express high levels of IL-1 receptor
antagonist (IL-1ra) when treated with IL-1, leading to loss of
modulation of IL-1 action. This can be overcome by transiently
transfecting cells with IL-1ra. Thus a decreased level of IL-1ra
expression in orbital fibroblasts may underlie the exaggerated
responses to IL-1 observed in those cells and, therefore, the
susceptibility of the orbit to inflammation.
ophthalmopathy; inflammation; Graves' disease; cytokine
