Bone and Joint Research Unit, John Vane Building, St. Bartholomew's and Royal London School of Medicine, Charterhouse Square, London, United Kingdom
Address for correspondence: Ian C. Chikanza, M.D., F.R.C.P., Bone and Joint Research Unit, John Vane Building, St. Bartholomew's and Royal London School of Medicine, Charterhouse Square, London EC1M 6BQ, U.K. Voice: 44-207-882 6123; fax: 44-207-882 6121.
i.c.chikanza{at}gmul.uk
Ann. N.Y. Acad. Sci. 966: 39-48 (2002).
Corticosteroids (CSs) have potent immunosuppressive effects
and are commonly used to treat a range of immunological and
inflammatory diseases such as rheumatoid arthritis (RA). These
effects are mediated by the ability of CSs to modulate gene
expression. CSs act by binding to the CS receptor (CR), which
exists as
and ß isoforms. Only CR
binds CS. CRß
functions as an endogenous inhibitor of CS and is expressed
in several tissues. The CS/CR
complex binds to the glucocorticosteroid
response element in the nucleus and also interferes with AP-1
and NF-
B binding. Thus, CSs inhibit the transcription of AP-1
and NF-
B inducible genes, such as interleukin (IL)-2, IL-6,
IL-8, IL-1ß, and tumor necrosis factor (TNF)
, as
well as T-cell proliferation. In clinical practice, a proportion
of RA patients do not respond adequately to CS therapy. On this
basis, RA patients can be divided on clinical grounds and on
the ability of CSs to inhibit concanavalin A (conA)-induced
peripheral blood T-cell proliferation
in vitro into CS-sensitive
(SS) and CS-resistant (SR) subgroups. The
in vitro defined SS
and SR subgroups correlate with the clinical responses to CS
therapy. The mechanisms of the SR in RA patients remain unknown
but may include the following: dysregulation of CR
function,
alterations in the intracellular signaling mechanisms and/or
utilization of various other cellular activation pathways, perturbations
of the cytokine milieu, and inhibition of lipocortin. In SR
subjects, CSs fail to significantly inhibit conA-induced IL-2
and IL-4 secretion
and LPS-induced IL-8, IL-1ß secretion
in vitro. CS therapy fails to reduce the circulating levels
of IL-8, IL-1ß, and TNF
in SR RA patients. Peripheral
blood mononuclear cells (PBMCs) from SR significantly overexpress
activated NF-
B and I
B
.
In vitro CSs fail to significantly inhibit
conA-induced NF-
B activation in PBMCs from SR RA patients. Our
preliminary observations show enhanced CRß expression
by PBMCs from SR RA patients. It is most likely that other molecular
mechanisms such as enhanced AP-1 expression are involved, and
we currently are investigating such possibilities.
