ARTICLE
THE INTERLEUKIN-1 FAMILY
Interleukin-1 (IL-1; compare [1] for a detailed survey of the literature)
is a constituting member of the interleukin family of cytokines. Originally
IL-1 was described as a monocyte-derived activator of T cells and termed
lymphocyte activating factor (LAF). It finally turned out that IL-1 was
identical to other activities described previously, such as endogenous
pyrogen (EP), leucocyte endogenous mediator (LEM), epidermal cell-derived
thymocyte activating factor (ETAF), catabolin, serum amyloid A inducer,
or B cell activating factor (BAF). Besides monocytes, B cells, hematopoietic
progenitor cells, polymorphonuclear granulocytes (PMN), keratinocytes,
fibroblasts, or epithelial cells produce IL-1. Production is induced by
numerous stimuli including bacterial products, phagocytosis, complement
components, viruses, cytokines themselves, or oxidized LDL. Interleukin-1
is a pluripotent central mediator of the cytokine network involved in
countless biological functions in the immune system, as well as during
infection and inflammation, cell-differentiation, tissue remodelling,
and even cell death. Many of the functions of interleukin-1 are mediated
by potent induction of the production of secondary cytokines, such as
IL-6 or CSF's.
The two isoforms of IL-1 (IL-1a and IL-1b) are produced as precursor
molecules (31 kDa), which are enzymatically processed into their mature
forms (17 kDa). Both precursors are present in the cytosol and the IL-1a
precursor is also expressed on the cell surface. The IL-1a precursor is
functionally active, whereas the IL-1b precursor is not. Most of the IL-1a
activity remains cell-associated, whereas most of the IL-1b activity is
released. IL-1 has been cloned a decade ago and the described clones represented
the two isoforms of IL-1. The IL-1 genes are located at the chromosome
2 (2q14-2q21) and may be derived from a prointerleukin-1a gene during
evolution. The minimum length for biological activity of IL-1b is amino
acid 120 to 266, and for IL-1a is amino acid 128 to 267. The IL-1 isoforms
are composed of 12 b-sheets, exhibiting a tetrahedron-like secondary structur
similar to basic fibroblast growth factor. Thus, IL-1 and FGF are thought
to possess a common ancestral gene.
The IL-1 receptor antagonists, two receptors and receptor-associated
proteins also belong to the IL-1 family of proteins (for a more detailed
summary compare [2-8], respectively). The soluble forms of IL-1 receptor
antagonist (IL-1Ra; 22-25 kDa) contains a leader sequence and is released
from the cells. However, a differentially spliced form of IL-1Ra lacking
a leader sequence is not released from the cells. This intracellular IL-1Ra
(icIL-1Ra) is not glycosylated and has a molecular weight of 18 kDa. Two
separate promoters control the expression of the soluble (PS)
and intracellular (PIC) IL-1Ra gene. The IL-1Ra's block the
IL-1 activity and IL-1Ra does not have agonist activity by itself. Interestingly,
mutation of amino acid 145 (Lys to Asp) in the IL-1Ra converts the antagonist
to a partial agonist. It has been shown recently that this amino acid
is not involved in binding to the receptor, but may be important for binding
to the accessory protein(s). So far two IL-1 receptors (80 kDa or 68 kDa)
are described and termed type I and type II IL-1 receptors. These molecules
belong to the family of immunoglobulin-like receptors, consisting of three
extracellular Ig-like domains, a transmembrane domain, and a cytoplasmatic
domain of 213 or 29 amino acids (type I or type II, respectively). All
three domains are necessary for high affinity binding of IL-1. In contrast,
the IL-1 receptor antagonist needs only domains 1 and 2 for high affinity
binding. It has been shown that the type II receptor binds IL-1, but does
not transduce a signal (decoy receptor) [6], whereas the type I receptor
is responsible for signalling. The IL-1b precursor does not bind to the
receptors, whereas the IL-1a precursor and both mature proteins do so.
This information is in accordance with the observation that IL-1a precursor
and the mature proteins are biologically active, whereas the IL-1b precursor
is not. Upon binding the IL-1 is internalized and translocated to the
nucleus. The IL-1 receptors can be shedded from blood cells and detected
in supernatants or body fluids in a soluble form [9]. Interestingly, viruses
can also produce soluble IL-1 receptor-like molecules, raising the possibility
that viruses may disturb regulation of the host defense system. Two more
IL-1 receptor family proteins are described, the receptor-associated protein
[7] and the IL-1 receptor-related protein [8]. The receptor-associated
protein is necessary for IL-1 responsiveness and it has been shown that
it is important for signal transduction, but not for binding of IL-1.
Signal transduction of
IL-1 receptors is summarized in a recent review in this Journal [10].
IL-1 CONVERTING ENZYME
AND THE CASPASE FAMILY
Interleukin-1 is produced as precursor molecule. Although a calcium
dependent protease (calpain; CANP) has been identified, that cleaves the
IL-1a precursor, the IL-1b cleaving protease (IL-1 converting enzyme (ICE)),
has received much more attention. Not least because ICE was the founding
molecule of a new family of proteases, the caspases [11] (Cystein containing
proteinases cleaving behind Asp). Identification of this enzyme unexpectedly
linked the IL-1 family to the apoptosis machinery, since it was discovered
that ICE and the cell death gene ced-3 of the nematode C. elegans
share 29% homology [12]. The ICE was first identified in THP.1 cells.
It is unique, in that it cleaves its substrate(s) behind Asp at P1. In
monocytes ICE is produced as a 45 kDa pre-form and subsequently processed
to two products of 19.8 kDa (p20) and 10.2 kDa size (p10). Processing
of the ICE precursor can be mediated by caspase 4 (TX) or may also take
place by autocatalytic processes. Two p20/p10 units combine to the proteolytically
active heterotetramer. Originally, the IL-1b precursor was thought to
be the only substrate of ICE. However, ICE is also capable of activating
the interferon-g-inducing factor (IGIF;
IL-18). Furthermore, ICE also cleaves a-actin, indicating a role of ICE
in apoptosis since actin cleavage may be important for both morphological
changes and regulation of DNA fragmentation [13]. However, a role of ICE
in apoptosis may be limited to certain cells [14], although overexpression
in fibroblasts induced apoptosis. Besides effects of ICE in apoptosis,
the IL-1 agonists themself may also contribute to induction of apoptosis
[15].
In addition to caspase 1, additional caspases are known (for review
compare [11]): A) the ICE-related subgroup with caspases 1, 4, 5, 11,
12, and 13. B) The ced-3-related subgroup(s), containing caspases
2 (which may form a third group by itself) as well as caspases 3, 6, 7,
8, 9, and 10, which are thought to be importantly involved in regulation
of apoptosis [16]. Caspase 3 appears to be a central player in apoptosis
cleaving proteins important for regulation of the cell integrity, DNA
repair or internucleosomal fragmentation. Function of ICE and other caspases
is modulated by inhibitory activities such as crmA, p35, or v-FLIPs,
other serpins, bacterial products, extracellular matrix, and the recently
discovered inhibitors-of-apoptosis (IAP's). It has been suggested that
mitochondria are importantly involved in regulation of apoptosis. Recently,
three molecules (APAF-1, -2, -3) have been identified, which activate
caspase 3 in the presence of dATP, suggesting an interference of mitochondria
and caspases. Interestingly, APAF-1 was the long sought homolog of ced-4
[17]. This molecule, like ced-4 in the nematode, is proposed to
form an "apoptosom" constituted of the three molecules Bcl-2, APAF-1,
and pro-caspase 3. Surprisingly, it turned out that APAF-2 was cytochrome
C released from mitochondria and that caspase 9 was APAF-3. Interestingly,
the release of of cytochrome C was shown to be important for activation
of apoptosis, and can be regulated by Bcl-2. Bcl-2 on the other hand may
be a substrate for caspase 3, raising the possibility of a regulatory
loop.
THE IL-1 AND THE CASPASE
FAMILIES IN DROSOPHILA
Defense systems appear to be present in all multicellular organisms,
with proteins containing domains present in IL-1 family proteins also
discovered in plants and invertebrates [18]. Among these organisms Drosophila
is of particular interest, since it is genetically well characterized.
In this organism IL-1-family-related molecules have been identified. In
particular the Drosophila transmembrane molecule Toll [19] containing
intracellular homology to the IL-1 receptor. It interacts with other molecules,
such as kinases (IRAK {Underlined: the molecules resembling the
mammalian counterparts of the Drosophila proteins}). This interaction
results in phosphorylation of cactus (I-kB) and subsequent release
of dorsal (NF-kB). Thus, the IL-1-induced reaction cascade resembles in
some aspects the spätzle-induced reaction cascade (spätzle,
Toll, cactus, dorsal). Interestingly, spätzle controls the antifungal
gene drosomycin in the fly. Furthermore, 43 kDa and a 60 kDa protein(s)
cross-reacting with IL-1a antibodies have been identified in Drosophila
embryonic muscles. Similarities to proteins of the caspase family and
inhibitors thereof have also been identified, pointing out, that similar
apoptosis mechanisms may act in Drosophila and men. Recently, it
has been shown, that the apoptosis molecule reaper in Drosophila
has similarities to the death domains in the TNF or Fas receptors, and
can activate ICE-like proteins [20]. Thus, Caenorhabditis elegans ced-3,
ced-4, and ced-9, resembling Drosophila melanogaster
reaper, grim, and hid, appear to parallel mammalian caspases, apaf's and
bcl's.
IL-1 IN THE CARDIOVASCULAR SYSTEM
Cardiovascular diseases are a major cause of death in the western societies.
In Germany more than 50% of mortality is caused by cardiovascular diseases.
The pathogenesis of many cardiovascular diseases is still not completely
understood. In the last decade a role of cytokines for cardiovascular
cell function and for development of cardiovascular diseases has been
proposed [21-25]. The data show that plasma levels of IL-6, IL-8, or TNF
are enhanced in some cardiovascular diseases, such as chronic heart failure,
cardiac surgery, myocarditis, or myocardial infarction. Evidence for the
role of cytokines in pathogenesis can also be derived from animal experiments
showing that overexpression of TNF resulted finally in congestive heart
failure [26]. However, only few informations exist regarding the endogenous
production and function of IL-1 family proteins and the associated enzyme(s)
of the caspase family in the cardiovascular system. In coronary angioplasty
supported by cardiopulmonary bypass IL-1 levels were not increased [27],
whereas IL-1Ra was enhanced (own unpublished data). The same situation
is present in myocardial infarction, although IL-1 may be present at a
very early state after infarction, a time point which has not been investigated
by all authors. Also, in congestive heart failure (CHF) we and others
did not detect IL-1 in the plasma [28], and these patients also had elevated
IL-1Ra levels (own unpublished results). In some patients with myocarditits,
but not with cardiomyopathy IL-1 was detected [29]. Although IL-1 is not
measured in large amounts in the serum, it has been found in cardiovascular
tissues [30-32]. These data and our findings, that smooth muscle cells
or cardiomyocytes produce IL-1 activity, but retain the IL-1 cell-associated
[33, 34] emphazise the hypothesis that in cardiovascular diseases IL-1
produced locally is of particular interest as a regulator of production
of further mediators, contractillity, or even cell death.
Functions of IL-1
in the cardiovascular system
Cytokines produced systemically, thus, present in the blood, may act
on cells of the blood vessels and the heart. The prove for this hypothesis
is still missing, although a number of publications provide evidence,
that cytokine plasma levels correlate with the severity of cardiovascular
diseases (summarized in [21-25]). On the other hand, cytokines produced
by cells in the vessel wall or the heart itself may act locally on adjacent
cells and contribute to pathogenesis of cardiovascular diseases. IL-1
is a central player in the cytokine network and is a multipotent cytokine.
It can induce a variety of functions in cells derived from the cardiovascular
system, including proliferation or cytokine production. Thus, a number
of investigators have identified cytokines produced by endothelial cells,
smooth muscle cells, or cardiomyocytes in cell culture. The IL-1, as well
as other cytokines produced in response to IL-1 in these cells, may be
important for regulation of cell growth, contractility, or death of cardiovascular
cells, but may also contribute to recruit and activate blood cells, such
as leukocytes or platelets. It has been shown that cultured cardiovascular
cells can produce IL-1 [35, 36], IL-6 [37-40], IL-7 [41], IL-8 or other
chemokines [42-44]. Since IL-1 is produced by cardiovascular cells itself
we and others have used co-culture systems to measure IL-1-mediated cell
interactions. Incubation of pretreated and fixed smooth muscle cells or
platelets bearing IL-1 surface activity with further viable cells resulted
in an enhanced IL-6 production in SMC [33, 45]. The coincubation experiments
with platelets also showed, that the platelet activator thrombin was sufficient
to induce cytokine production [45, 46]. IL-1 exerts negative inotropic
effects on heart cells and also inhibits contraction of SMC, the latter
by activation of guanylate cyclase in an NO-independent pathway [47].
There are also data available that NO-independent depression of contractility
exists in cultured cardiomyocytes. In addition, IL-1 may modify cardiac
function by phospholamban-mediated depression, by NO-mediated mechanisms,
or by reduced Ca++ current. It has also been described that
IL-1Ra, but not TNF antibodies reversed the inhibition of isoproterenol-induced
contractility caused by monocyte supernatants, indicating a potent role
for IL-1 in cardiodepression. Particular forms of hypertrophy may also
be induced by IL-1 [48]. Little is known about cardiovascular cells as
a source of IL-1Ra, however, in vitro experiments showed that IL-1Ra
can block activation of cardiovascular cells by IL-1. The intracellular
form of the IL-1Ra added to cell cultures inhibited endothelial production
of IL-6, IL-8, or MCP-1. IL-1Ra also blocked IL-1-induced SMC proliferation
or matrix metalloproteinase production in Mø-SMC coculture.
Characterization of IL-1 in the cardiovascular
system
The expression of cytokines in endothelial cells, smooth muscle cells,
and cardiomyocytes has been investigated during the last 10 or 15 years.
It has been shown in cell culture that endothelial cells [35], smooth
muscle cells [33, 36], as well as cardiomyocytes [34] can produce IL-1.
The IL-1 in these cells is not well characterized. We determined in Western
Blot analysis that human vascular smooth muscle cells expressed both IL-1
isoforms only in the precursor form (Figure
1). These data were consistent with the previous finding that
smooth muscle cells exhibited IL-1 activity on their surface that was
inhibited by an IL-1a antiserum [33]. Similar to SMC cardiomyocytes also
expressed IL-1 acitivity cell-associated [34]. These in vitro results
are paralled by investigation of cardiovascular tissues, showing that
IL-1b mRNA was present in atherosclerotic rabbit aortae [30], and in patients
with cardiomyopathy [32], or congestive heart failure [31]. The IL-1 mRNA
has been identified in endothelial cells and to a lower degree in smooth
muscle cells [32]. Another study showed that both endothelial cells and
cardiomyocytes in the rat heart expressed IL-1a. The IL-1 receptor antagonist
(IL-1Ra) in smooth muscle cells is expressed in its intracellular form
[49]. The IL-1 receptor on endothelial cells is the IL-1 receptor type
I [50]. The IL-1 binding activity on smooth muscle cells probably reflects
both types of IL-1 receptor, since we find mRNA for both type I and type
II in these cells (own unpublished data).
Caspases and apoptosis
in the cardiovascular system
The role of caspases and apoptosis in cardiovascular diseases such as
congestive heart failure, atherosclerosis, or myocardial infarction has
been recognized recently [51, 52]. However, the apoptotic mechanisms involved
in cardiovascular diseases still remain to be resolved in more detail.
It has been described that in endothelial cells TNF or mononuclear cells
can induce apoptosis and data have been provided that caspases as well
as adherens proteins may be involved in regulation of endothelial apoptosis
in vitro [53]. Also, in SMC apoptosis has been observed under pathological
situations [54] and some apoptotic molecules, such as Fas and c-myc,
have been identified [55, 56]. Furthermore, we detected caspase 1 in smooth
muscle cells and endothelial cells [57], and other groups found caspase
3-like activity in endothelial cells [58]. Also, in human atheromata ICE
was detected [59]. Studies with cardiomyocytes showed that apoptosis was
also observed under various conditions, and in rats reperfusion injury
and infarct size were reduced by caspase 3 inhibitors [60]. In addition
to the identification of ICE mRNA and immunoreactive protein we found
in vascular smooth muscle cells an inhibitor of IL-1b processing [57].
This inhibitory activity may be a smooth muscle cell specific ICE inhibitor
and, thus, reflect a tissue specific regulator of inflammatory and/or
apoptotic processes in cardiovascular tissues.
Taken together cardiovascular cells can produce cytokines necessary
for regulation of inflammatory processes, contractility, cell death or
other normal or pathological processes in the heart and the vessel wall.
Furthermore, informations are summarized, indicating that apoptosis is
involved in cardiovascular diseases, and that cardiovascular cells express
some molecules necessary for execution of apoptosis. However, the role
of cytokines or apoptosis for pathogenesis of cardiovascular diseases
is far from beeing understood.
CONCLUSION
Acknowledgement
This study was supported by grants of the Deutsche Forschungsgemeinschaft
to H. Loppnow
(Lo 385/1-1 and 4-1), as well as grants of the BMBF Forschungsverbund
Halle (Molecular mechanisms of cardiac overload) to K. Werdan and H. Loppnow
(BMBF Projekt 06).
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