Interleukin-1 receptor antagonist (IL-1ra; also known as
IL-1F3) is a 22-25 kDa member of the
IL-1 family of cytokines. Currently, there are 11 family
members (IL-1F1-F11), nine of which form
an IL-1 gene cluster on human Ch2 (1-3). Each IL-1 family
member contains an IL-1 fold. This
fold is generated by 12 packed beta -sheets that interact to
form a beta -trefoil structure. Little amino
acid (aa) homology is required to achieve this structure,
and this explains the low aa identity
among IL-1 family members. IL-1ra is a pure cytokine receptor
antagonist that has no signal
transduction-initiating activity (4). It is an acute phase
protein that exists to dampen
inflammation. IL-1( beta ) is initially produced by monocytes in
response to a variety of stimuli.
Circulating IL-1 then binds to widely expressed IL-1 type I
receptors (IL-1 RI) and initiates a
number of pro-inflammatory events. On endothelial cells
(EC), IL-1 induces PGE2 and IL-6
release, generating fever, thrombocytosis, and hepatic acute
phase protein production. In
synovial joints, IL-1 induces chondrocyte NO production, an
event that leads to reduced
collagen synthesis and chondrocyte apoptosis. Finally, IL-1
increases neutrophil counts, both in
blood and tissue, and thus is able to promote a
pro-inflammatory environment in multiple
locations (5-8). IL-1ra blocks IL-1 action through
competitive inhibition. More correctly,
although IL-1ra fills the IL-1 binding site in IL-1 RI, it
is also unable to orchestrate the creation of
a signal-transducing IL-1 RI:IL-1 R Accessory protein (IL-1
R AcP) heterodimer complex. Effective
IL-1ra concentrations are generally 100-fold greater than
local IL-1 concentrations. This is
because the IL-1ra half-life is but 6 minutes, and very few
IL-1 type I receptors need to be
engaged by IL-1 to elicit a cellular response (5, 7, 9).
Human IL-1ra is synthesized as a 177 aa precursor that
contains a 25 aa signal sequence and a
152 aa mature region (10, 11). Although it contains an IL-1
cytokine fold, it apparently lacks two
structural motifs that allow for activation of the IL-1
receptor heterodimer. First, and following
binding to IL-1 RI, the presence of Ile 51-His 54 and Lys
145 of the mature molecule preclude
recruitment of IL-1 R AcP. Second, there is no identifiable
C-terminal lectin segment that is
hypothesized to help recruit an accessory signaling
component (1, 12, 13). Mature human
IL-1ra is 77% and 82% aa identical to mouse and canine
IL-1ra, respectively, and human IL-1ra
inhibits IL-1 activity on mouse cells (10). A number of cell
types express IL-1ra, including
monocytes (11), Sertoli cells (14), hepatocytes (15),
adipocytes (16), synovial fibroblasts (17),
mast cells (18), pancreatic beta -cells (19), and intestinal
epithelial cells (20). There are at least three
intracellular IL-1ra isoforms (icIL-1ra1, 2, and 3). All
show N-terminal variation, and all contain
amino acids 35-177 of the secreted precursor (21-23).
Intracellular IL-1ra1 is of particular
interest, because it is reported to be "secreted"
by endothelial cells and binds to the IL-1 RI in
an antagonist fashion (23-25). Intracellular IL-1ra1 is 159
aa in length and shows a 3 aa
substitution for the first 21 aa's of the signal sequence of
IL-1ra (21).