(Journal of Leukocyte Biology. 2001;69:197-206.)
© 2001
by Society for Leukocyte Biology
More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control
Ute Bank and
Siegfried Ansorge
Institute of Immunology, Otto von Guericke University Magdeburg, Germany
Correspondence: Dr. U. Bank, Institute of Immunology, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg, Germany. E-mail: ute.bank{at}medizin.uni-magdeburg.de
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ABSTRACT
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In addition to the mechanisms inducing the expression and secretion of
cytokines under distinct pathophysiological conditions, the fate of
cytokines after secretion at sites of inflammation is a field of
growing interest. Proteolysis has been suggested to be a fundamental
mechanism of regulating the activities of various components of the
cytokine network. Evidence grows that besides highly specific cytokine
converting proteases such as interleukin-1ß-converting enzyme or
tumor necrosis factor-converting enzyme, neutrophil-derived serine
proteases are intimately involved in the modulation of the activities
of cytokines and their receptors. Particularly at sites of
inflammation, high amounts of the active serine proteases elastase,
cathepsin G, and proteinase 3 are released from infiltrating
polymorphonuclear cells in close temporal correlation to elevated
levels of inflammatory cytokines, strongly indicating that these
proteases are involved in the control of cytokine bioactivity and
availability.
Key Words: elastase • proteinase 3 • cathepsin G • interleukins • growth factors
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INTRODUCTION
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The major physiological function of the neutral serine proteases
elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR3) stored in
the azurophilic granules polymorphonuclear neutrophils (PMN) as active
enzymes, is commonly thought to be the intralysosomal degradation of
engulfed cell debris or microorganisms. Given the acidic milieu within
the phagolysosomal compartment, it has been questioned whether
intralysosomal proteolysis is indeed the major function of these
enzymes having an activity optimum around neutral pH values (for
overview see Table 1
) [1
]. Moreover, since it was recognized that the
extracellularly released PMN-serine proteases may escape from
inhibition and are proteolytically active outside the cell, the
interest in the function of these enzymes within the extracellular
milieu has remarkably increased [2
, 3
]. It
soon became evident that HLE, Cat G, and PR3 play crucial roles in
extracellular proteolytic processes at sites of inflammation. Until
recently, most studies had focused on the deleterious potential of
PMN-derived serine proteases at foci of inflammation, which are mainly
attributed to their matrix-degrading activity [4
5
6
].
However, over the past few years evidence has accumulated that various
bioactive proteins are natural substrates of these proteases too. This
led to the hypothesis that extracellularly released PMN-serine
proteases have active regulatory functions in local inflammatory
processes [7
].
Here, we intend to focus attention on a particularly intriguing aspect
of PMN-serine protease activity: the proteolytic modulation of cytokine
bioactivities. Under certain pathophysiological conditions PMN-derived
proteases may function alternatively to unique, cell-associated
cysteine or metalloproteases, which represent the classical pathways of
cytokine processing by catalyzing the conversion of inactive cytokine
precursors or the solubilization of membrane-bound cytokines and
receptors. The most prominent examples of these highly specific
cytokine-processing enzymes are the interleukin-1ß
(IL-1ß)-converting enzyme (ICE, caspase-1) and the tumor necrosis
factor (TNF)-converting enzyme (TACE) [8
,
9
]. However, this aspect of PMN-protease activity seems
to be not commonly appreciated despite the wealth of reports published
in this field during the last decade.
This review summarizes the present knowledge regarding interactions of
PMN-serine proteases with the cytokine network, comprising (1) the
direct proteolytic modulation of the bioactivities of active
inflammatory cytokines, (2) the release of active cytokines from their
inactive precursors, (3) the cleavage of cell surface-bound cytokine
receptors, and (4) the proteolysis of cytokine binding proteins
(Fig. 1
). The possible consequences for the course of inflammatory
processes as well as the relevance of these findings for the
measurement of cytokine concentrations and bioactivities will be
discussed.
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Figure 1. Cytokine bioactivity control by PMN-derived serine proteases and the
biological consequences on neutrophil function. (A) The
immunostimulating cytokines IL-6, TNF- , and IL-2 are rapidly
inactivated by HLE, PR3, or Cat G. The inactivation of these cytokines
limits their immunostimulatory activities, especially an ongoing
cytokine-mediated PMN activation (negative feedback loop). In addition,
the PMN-serine protease-generated cytokine fragments may function as
antagonists of the active cytokines, as shown in case of IL-2. (B)
Beyond this, the PMN-serine protease-catalyzed cytokine receptor
shedding (IL-6R and TNF-RII) may down-regulate the PMN responsiveness
to proinflammatory cytokines. On the other hand, soluble forms of
cytokine receptors were found to protect their ligands from proteolytic
degradation. (C) The processing of cytokine precursors or latent
cytokine forms by PMN-serine proteases, which results in the activation
of PMN-attracting or -stimulating cytokines such as IL-1ß, TNF-,
TGF-ß, or IL-8, contributes to the reinforcement and perpetuation of
PMN-dominated inflammatory processes. Taken together, this scheme
demonstrates the complex biological consequences of PMN-protease action
only with regard to the cytokine-mediated regulation of neutrophil
function. The PMN-serine protease effects on the several components of
the cytokine network in their entirety might disturb the tender balance
of pro- and anti-inflammatory cytokines at sites of inflammation.
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CLEAVAGE OF ACTIVE CYTOKINES BY PMN-DERIVED SERINE PROTEASES
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Because HLE, PR3, and Cat G belong to the group of
endoproteolytic enzymes with a comparatively broad substrate
specificity (Table 1) [10
11
12
], it is widely held that
these enzymes are capable of cleaving nearly all proteins in an
unspecific manner. Most cytokines contain numerous putative cleavage
sites for these proteases, strongly suggesting that they represent
natural substrates. Because proinflammatory cytokines are particularly
found simultaneously with increased amounts of active PMN-proteases
[13
14
15
16
17
18
], most of the studies about
PMN-protease-cytokine-interactions have focused on prominent
inflammatory cytokines, such as TNF-, IL-6, and IL-8. The first
evidence for a direct influence of PMN-serine proteases on cytokine
bioactivities came from in vitro studies, demonstrating the
rapid degradation of the mature 17 kDa TNF- molecule by supernatants
of activated PMN as well as by purified NE and Cat G
[19
20
21
]. The proteolytic cleavage of TNF- into at
least two fragments results in the loss of its cytotoxic activities.
Likewise, it has been shown that PMN-derived serine proteases are
capable of inactivating the pleiotropic cytokine IL-6
[22
23
24
]. Recent results provide evidence that each of
the three PMN-serine proteases has the capacity to catalyze the rapid
fragmentation of IL-6 at sites of inflammation, although these enzymes
initially attack different peptide bonds within the IL-6 molecule
[24
]. It is interesting to note that the complexation of
IL-6 with the soluble forms of the IL-6 receptor subunits (gp80 and
gp130), originally thought to function as carrier proteins protecting
the molecular integrity of the cytokine, only prevents the inactivation
of IL-6 by Cat G. This corresponds with the finding that Cat G cleaves
preferentially the Phe78-Asn79 bond, which is
directly involved in the binding of IL-6 to the IL-6 receptor gp80
chain.
The relevance of the PMN-serine protease-catalyzed TNF- and IL-6
inactivation to inflammatory processes in vivo is strongly
supported by the fact that in various inflammatory exudates or in sera
from septic patients with high PMN-serine protease activities the
bioactivities of these cytokines were found to be dramatically reduced
[16
, 24
]. The biological consequences of
the inactivation of both cytokines at sites of inflammation are
difficult to assess, especially in the case of IL-6, which elicits
proinflammatory as well as anti-inflammatory effects. In consideration
of the fact that both cytokines were previously identified as potent
activators of neutrophils [18
, 25
26
27
],
their rapid inactivation by PMN-derived proteases might represent a
negative feedback loop, which limits neutrophil activation (Fig. 1)
. On
the other hand, the combined inactivation of IL-6 and TNF- prevents
the acute phase response [28
]. With regard to the
function of IL-6 as a key cytokine for the induction of
immunosuppressive mediators [29
], it is conceivable that
the IL-6 inactivation at sites of inflammation results in strengthening
and perpetuation of the inflammation.
The immunostimulatory cytokine IL-2, which is mainly known as a potent
T cell activator but that also affects neutrophil function
[30
, 31
], was identified as a further
natural substrate of HLE [32
]. Three of the at least
eight cleavage products were reported to antagonize the proadhesive
activities of IL-2, thereby preventing the extravasation of T cells as
well as the neutrophil adherence. It has been conclusively shown that
these proteolysis products of IL-2 represent natural feedback
inhibitors of inflammation [32
]. A similar function of
fragments from TNF- or IL-6 is conceivable, but has not been proven
as yet.
Although the loss of bioactivity of TNF-, IL-6, or IL-2 still could
be considered as a consequence of unspecific degradation, there is a
clear regulatory effect of distinct PMN-serine proteases with regard to
active CXC-chemokines: their limited proteolysis by PMN serine
proteases was found to result in an enhanced neutrophil-stimulating
activity. Padrines et al. demonstrated that PR3 specifically catalyzes
the release of a more active amino-terminal truncated form (70 amino
acids) from the mature IL-8 molecules (77 amino acids)
[33
], whereas HLE was reported to inactivate IL-8 or to
have no effect on its bioactivity, respectively [23
,
34
]. A similar activity-enhancing mechanism was reported
for the epithelial cell-derived neutrophil-activating protein-78
(ENA-78), which stimulates neutrophil chemotaxis and degranulation: a
stable amino-terminal truncated ENA-fragment (ENA 9–78) released by
Cat G has a twofold higher chemotactic activity and an elevated
elastase-releasing activity than the full-length ENA-78 molecule
[35
]. It is interesting that the ELR-motif preceding the
first cysteine residue, which is critical in defining the
neutrophil-activating properties of the CXC-chemokines IL-8 and ENA-78,
remains after the proteolytic processing. According to these data, it
is conceivable that the enhancement of the neutrophil-activating
potency of these chemokines by PR3 or Cat G might represent a common
physiological regulatory principle for this class of chemokines. The
question of whether the bioactivities of other structurally related
CXC-chemokines, such as CGP-2 or GRO-, -ß, or -
, could be
augmented by limited amino-terminal processing, remains to be
elucidated.
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PMN-PROTEASE CATALYZED RELEASE OF ACTIVE CYTOKINES FROM PRECURSOR
MOLECULES
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Even before the metalloproteinase TACE and the cysteine proteinase
ICE were identified as specific convertases catalyzing the release of
active soluble TNF- or IL-1ß from their inactive precursor
molecules [36
, 37
], in vitro as
well as animal studies provided the first hints for a crucial
pathophysiological role of other proteases, including PMN-derived
serine proteases in the activation of these cytokines
[37
38
39
40
41
42
].
Recent results strongly suggest that PR3 plays a critical role in this
alternative activation of membrane-anchored pro-TNF- or released
pro-IL-1ß, even though it shares many enzymatic characteristics with
HLE. In spite of the quite similar substrate specificities of both
enzymes, PR3 was found to be much more potent in converting the
inactive precursors of TNF- and IL-1ß into the bioactive soluble
cytokines [43
, 44
]. In both the IL-1ß and
TNF- precursor molecule, a valine-arginine bond in immediate
vicinity to the previously described ICE and TACE cleavage sites is
cleaved by PR3. However, the fact that the PR3-hydrolyzed peptide bonds
within the IL-1ß and TNF- precursors are not identical to the ICE
and TACE cleavage sites (Fig. 2
), does not significantly affect the activity of the mature
cytokine molecules. Thus, it is highly probable that this accessory
mechanism of TNF- or IL-1ß activation is particularly operative at
sites of inflammation [44
].
Lately, the inactive precursor of IL-18, the most recently classified
interleukin so far, was identified as a substrate of proteinase 3
[8
, 45
]. IL-18 shares many structural and
regulatory features with IL-1ß [46
]. As is the case
for pro-IL-1ß, the IL-18 precursor can be activated by the ICE
[8
], but particularly in infections PR3 is suggested to
represent a major IL-18 activator. Taken together, these findings might
be the basis for defining the physiological PR3 function distinct from
that of HLE [44
]. Because PR3 is the target antigen of
the c-ANCA autoantibodies in Wegener’s granulomatosis, a severe
Th1-dominated autoimmune disease with strong cellular dysregulations,
the special role of this protease in cytokine activation is of
particular interest.
In addition, HLE and Cat G have been implicated in the activation of
other growth factors, which are synthesized as transmembrane
precursors, such as transforming growth factor ß (TGF-ß), and
endothelial-derived growth factor (EDGF) [47
,
48
]. Additional regulatory mechanisms involving PMN
serine proteases seem to be modifications of bioactivity profiles by
proteolytic processing of distinct cytokine precursors. For example,
Cat G has been known to catalyze the release of the platelet-derived
growth factor (PDGF), chemotactic for fibroblasts and monocytes,
whereas HLE releases a PDGF molecule lacking the fibroblast-attracting
activity [49
]. In addition, the Cat G-catalyzed
sequential degradation of the platelet-derived connective tissue
activation protein-III (CTAP-III, 85 amino acids) to
ß-thromboglobulin (ß-TG, 81 amino acids) and subsequently to the
neutrophil-activating protein-2 (NAP-2, 70 amino acids) may be
considered as a prime example for such a process
[50
51
52
]: whereas the multifunctional CTAP-III is known
to act mainly as a fibroblast-activating cytokine, the bioactivities of
the amino-terminal truncated, Cat G-generated cleavage products ß-TG
and NAP-2 shift toward neutrophil chemotaxis and stimulation. By
generating these potent PMN chemoattractants and activators, activated
Cat G-releasing PMNs present at local sites of inflammation may
contribute to an ongoing attraction, extravasation, and activation of
circulating PMNs. On the other hand, functional studies revealed that
during the course of Cat G-catalyzed CTAP-III conversion into NAP-2,
the high-affinity CXC-chemokine receptor-2 (CXCR-2) is down-regulated
on the surface of activated PMNs. Thus, the proteolytic generation of
NAP-2 does not result in a further enhancement of the present PMN
activation, but renders the cells increasingly insensitive toward
stimulatory effects of all CXCR-2 ligands [53
]. Because
Cat G is released from highly activated, infiltrated PMNs, their
desensitization via the Cat G-catalyzed NAP-2 formation makes sense,
from a teleological point of view, because it prevents an ongoing PMN
activation at sites of inflammation. Finally, it should be noted that
in contrast to Cat G, elastase action on CTAP-III results in the
release of inactive chemokine fragments [50
].
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ALTERNATIVE PATHWAY OF CYTOKINE RECEPTOR-SHEDDING
|
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Another important mechanism for controlling cytokine bioactivities
is the modulation of functional cytokine receptors at the surface of
the target cell. The proteolytic solubilization of the ligand-binding
cytokine receptor ectodomains not only renders cells insensitive toward
cytokine effects. The capacity of soluble cytokine receptor forms to
bind their ligands may prolong the cytokine half-life time or prevent
the cytokine binding to cell-bound receptors [54
,
55
]. Whereas highly specific membrane-anchored
metalloproteinases have been favored to catalyze the proteolytic
cleavage of cytokine receptors in response to the activation of the
receptor-bearing cell, evidence has accumulated that other classes of
ectopeptidases are implicated in the receptor-shedding at sites of
inflammation [56
57
58
] (Fig. 3
). The close temporal correlation between the concentration changes
of PMN proteases and distinct soluble cytokine receptors in
inflammatory processes pointed to a putative role of PMN-derived serine
proteases [59
, 60
]. In vitro
data published by Porteu and collaborators in 1991, provided direct
evidence for the involvement of HLE in the TNF receptor-shedding
[61
]. HLE was reported to generate a ligand-binding
fragment of the 75-kDa TNF-R, the type of TNF receptor predominantly
expressed on myeloid cells. Because the soluble TNF-R affects the
TNF-mediated cellular activation as well as its cytotoxic effects
[62
], the HLE-catalyzed TNF-R-shedding is believed to
represent an accessory mechanism for controlling the cellular responses
to TNF at sites of inflammation. In spite of these data, the
involvement of PMN-serine proteases in cytokine receptor shedding
processes has received little attention for several years. Interest has
been renewed after the identification of a number of cell surface-bound
receptors such as the complement receptor-1, the lipopolysaccharide
(LPS) receptor (CD14), the T cell antigens CD2, CD4, and CD8, or
several adhesion molecules (ICAM, CD23) as substrates of PMN-serine
proteases [63
64
65
66
67
68
]. Recently, the potent effects of the
three PMN-serine proteases on the cell surface-bound ligand-binding
chains of IL-2 and IL-6 receptors were described [60
].
The concentrations of both the soluble IL-6R gp80 chain and the soluble
IL-2R rise in close temporal correlation to the elevated protease
release from PMN at sites of inflammation. Under in vitro
conditions, the cleavage of the IL-2R was found to be predominantly
catalyzed by HLE and, to a lesser extent, by PR3, whereas the IL-6
receptor gp80 ectodomain was found to be exclusively cleaved off by Cat
G. As is the case for the HLE-shed TNF receptor fragment, the
PMN-protease-released soluble IL-6R and IL-2R molecules gain functional
significance because they have retained their ligand-binding capacity.
These data imply that under certain conditions PMN serine proteases
indeed may significantly affect the cellular responsiveness to
cytokines (Fig. 3)
. It should be emphasized that in contrast to the
metalloproteinase-catalyzed process, which depends on the activation of
the receptor-bearing cell, this alternative pathway of receptor
shedding is independent of the cellular activation state.
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Figure 3. Alternative pathway of IL-2R, TNF-RII, and IL-6R shedding by PMN-serine
proteases and the putative functional consequences. (A) The cleavage of
the IL-2R ectodomain prevents the formation of the high-affinity IL-2R
heterotrimer. Binding of IL-2 to sIL-2R reduces the cellular
availability of IL-2. (B) HLE cleaves the p75-TNF-R ectodomain, thereby
blocking cellular TNF effects. (C) Cat G cleaves the IL-6R gp80 chain
near the plasma membrane. The WSXSW motif remains intact, thus allowing
the binding of IL-6. The binding of sIL-6R/IL-6 complexes to the gp130
signal transduction molecule results in IL-6 signal transduction.
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|
A number of cytokine receptors share structural features with the
above-mentioned PMN-protease-cleavable receptor molecules. Thus it is
highly conceivable that they are also hot candidates to be shed via
this alternative pathway. In particular, putative effects of PMN
proteases on the signal-transducing common cytokine receptor chains
such as gp 130 or the IL-2 receptor- chain, which are also found in
elevated amounts in inflammatory diseases [69
70
71
],
remain to be elucidated. Because common chains are shared by different
members of a given cytokine receptor family, their shedding should have
far-reaching regulatory consequences.
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PROTEOLYSIS OF CYTOKINE BINDING PROTEINS
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Some growth factors, such as TGF-ß or insulin-like growth factor
(IGF), circulate in latent forms, which are incapable of binding to
their receptors. These growth factors are complexed with distinct
binding proteins that have to be removed in order to release the
biologically active growth factor. The activation mechanisms are not
fully understood, but there is evidence that PMN-serine proteases are
implicated in the activation of latent growth factors at sites of
inflammation (Fig. 4
) [72
73
74
75
]. By far the highest attention was given
to the activation of the TGF-ß isoforms, pleiotropic cytokines with
pro- and anti-inflammatory properties. The three mammalian forms of
TGF-ß identified to date are highly homologous and probably activated
by similar mechanisms [76
]. High-molecular-weight latent
TGF-ß complexes are present in large amounts in the circulation and
consist of the mature 25-kDa TGF-ß dimer and at least two associated
binding proteins. The so-called latency associated protein (LAP), a
homodimer of the intracellularly cleaved off amino-terminal part of the
TGF-ß precursor, has been suggested to clutch the active TGF-ß
molecule. The proteolytical cleavage of LAP is thought to result in the
opening of the molecular LAP clamp. PR3 can potently activate TGF-ß
at sites of inflammation [73
]. A marginal activation of
TGF-ß by HLE and Cat G was observed [73
,
77
]. TGF-ß2 was recently found to be
synthesized and subsequently activated by stimulated PMN
[74
]. Our own preliminary data support the notion that
PR3 and HLE are capable of efficiently cleaving LAP, whereas the mature
TGF-ß1 molecule seems to be resistant against these
proteolytic activities [unpublished observations]. In contrast,
TGF-ß3 was described to be proteolytically inactivated by
HLE [78
].
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Figure 4. Growth factor control by PMN-serine proteases via cleavage of growth
factor binding proteins exemplified for TGF-ß. The latent TGF-ß
complex consits of the mature TGF-ß homodimer, the latency-associated
protein (LAP) and a latent TGF binding protein (LTBP). The LTBP, which
mediates the ECM association of latent TGF, is hydrolyzed by HLE. PR3
is highly potent in activating the TGF-ß/LAP complex.
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Other TGF-ß binding proteins designated as latent TGF binding
proteins 1–4 (LTBPs) are also substrates for HLE [77
,
79
, 80
]. The LTBP molecules, which are
covalently bound to the LAP dimers via a disulfide bond, mediate the
linkage of TGF-ß-LAP complexes to the extracellular matrix (ECM). By
cleaving these molecules, HLE may cause the rapid release of ECM-bound
TGF-ß in inflammatory processes. It is interesting to note that LTBP
molecules are structurally homologous to the fibrillin group of ECM
proteins. As a result of this special structural feature of LTBP it
might not be surprising that HLE, one of the most potent ECM-degrading
proteases, is capable of hydrolyzing these proteins.
As another example, the availability and bioactivity of the
insulin-like growth factor (IGF) has been shown to be under control of
PMN-serine proteases [81
]. Both HLE and Cat G cleave
each of the known IGF-binding proteins (IGFBPs), which also mediate the
association of IGF complexes to ECM components [82
,
83
]. Both enzymes hydrolyze the IGFBPs in
vitro and in vivo more effectively than other
previously described IGFBP-degrading proteases [81
].
Whereas Cat G preferentially attacks the IGFBP-5, followed by BP-2,
BP-3, BP-4, BP-1, and BP-6, elastase most effectively catalyzes the
cleavage of IGFBP-3 and IGFBP-4, followed by BP-1, BP-5, BP-6, and
BP-2. In contrast to Cat G, HLE was additionally found to convert the
free IGF-I into a smaller fragment in vitro. This suggests
unique functions of each PMN-protease in the regulation of IGF
activities during inflammation and wound healing [81
].
In addition, the PMN-serine proteases were found to regulate the
bioactivity and availability of active growth factors bound to ECM
proteins. In this respect the matrix-degrading capacity of these
enzymes is of direct importance: by cleaving heparan sulfate
proteoglycans, which function as growth factor co-receptors, the
PMN-serine proteases cause an enhanced release of ECM-bound growth
factors such as basic fibroblast growth factor (b-FGF) and TGF-ß
[74
, 76
, 83
84
85
86
87
]. The matrix
binding of these growth factors is thought to facilitate their rapid
local availability and prolong their half-life time. Thus, it is likely
that the protease-induced enhancement of growth factor availability is
involved in the pathogenesis of several fibroproliferative disorders
and in the development of atherosclerotic lesions [85
,
86
], which include a PMN-triggered inflammatory
component.
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CONCLUDING REMARKS
|
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Proteolysis has emerged as an important regulatory mechanism
within the cytokine network. The series of examples, delineating
the direct impact of the PMN-derived serine proteases on the cytokine
network, clearly shows that these enzymes are indeed more than
destructive and strongly supports the hypothesis that these enzymes
play a regulatory role in inflammatory processes. The specific and
restricted effects of HLE, Cat G, and PR 3 on distinct cytokines,
cytokine receptors, and binding proteins, as well as the finding that
other constituents of the cytokine network are remarkably resistant to
PMN serine protease activities, clearly contradicts the prevailing view
that these enzymes lack any specificity.
Distinct mechanisms allow the PMN-derived serine proteases to escape
from inhibition by endogenous serine protease inhibitors, particularly
at sites of inflammation. A fraction of extracellularly released
proteases rebinds to the PMN surface, allowing them to be locally
concentrated and protected from inhibition [2
,
88
]. Thus, it is likely that PMN-proteases function as
accessory proteases in the processing of cytokines, cytokine receptors,
and binding proteins, thereby being a part of the physiological
repertoire of cytokine bioactivity control mechanisms, especially in
PMN-dominated inflammatory processes.
It is interesting that a number of cytokines affected by these enzymes
elicit direct neutrophil-stimulating or -chemoattracting activities
(Table 2
). The inactivation of some PMN-stimulating cytokines such as
TNF- or IL-6 by proteases released from activated neutrophils might
represent a direct feedback mechanisms toward neutrophil function,
resulting in the limitation of neutrophil activation at sites of
inflammation. Thus, a limited and controlled extracellular activity of
PMN-derived serine proteases seems be essential for the physiological
control of inflammatory processes. However, a number of the described
PMN-protease-catalyzed cytokine modifications, such as the inactivation
of immunostimulatory cytokines or the cytokine receptor shedding, at
first sight are potentially anti-inflammatory. On the other hand, the
activation of other PMN-attracting or -stimulating cytokines by these
proteases, such as IL-1ß, IL-8, and TGF-ß, might contribute to the
enhancement and perpetuation of inflammatory processes (Table 2)
. It is
interesting that excessively high NE concentrations at sites of
inflammation and in the circulation were found to be closely associated
with a poor outcome for polytraumatized or septic patients
[89
, 90
]. In particular, an enhanced
PMN-protease release in the later phase of the inflammatory process
(>day 5) appears to have detrimental consequences [89
,
90
]. It is likely that a PMN-protease-induced disturbance
of the balance between pro- and anti-inflammatory cytokine effects
plays a crucial role for this phenomenon. Yet it is difficult to assess
the possible pathophysiological consequences of the wealth of various,
apparently contradictory, PMN-protease activities within the cytokine
network. This might even be true by closer consideration of the effects
of PMN-protease action on one distinct cytokine-cytokine receptor
system, as the example of IL-6 and its receptor system impressively
shows. The inactivation of IL-6 abolishes both its immunostimulatory
activities as well as its important function as key cytokine for the
induction of immunosuppressive mechanisms, which is essential for the
resolution and termination of an inflammatory process. It is likely
that particularly an excessive and prolonged activity of these
proteases may cause severe dysregulations within the cytokine network,
and secondary tissue damage, which tends to reinforce inflammatory
processes.
It is important to note that the knowledge about the proteolytic
modifications of cytokines summarized here should have practical
consequences in the determination of cytokine concentrations and
bioactivities. In particular, measurements of cytokine concentrations
or bioactivities in samples with high proteolytic (and oxidative)
activity, such as body fluids from sites of inflammation, require
special precautions. It has to be taken into consideration that the
results of cytokine immunoassays as well as bioassays might be affected
by the presence of active proteolytic enzymes in the sample, as well as
by several proteolytically generated cytokine binding proteins or
immunoreactive cytokine fragments [91
92
93
]. This was
clearly demonstrated by the discrepancies between the immunoreactive
levels and the bioactivities of IL-6 or TNF- in inflammatory
exudates [16
, 24
].
Finally, it is important to note that interactions between
PMN-proteases and the cytokine network are even more complex than
discussed here. PMN-serine proteases, in free as well as in their
inhibitor-complexed form, have been reported to induce the synthesis
and secretion of various inflammatory cytokines [23
,
94
95
96
97
98
]. For example, HLE, which is present in large
amounts in the respiratory epithelial lining fluid of patients with
cystic fibrosis, was found to cause an increased IL-8 gene
transcription, the accumulation of specific mRNA transcripts, and
release of IL-8-like neutrophil chemotactic activity in human bronchial
epithelial cells [97
]. PR3 and HLE, but not Cat G, are
capable of enhancing the IL-8 production by endothelial cells, thus
contributing to a self-perpetuating process of neutrophil recruitment
in acute inflammation [98
]. Cat G-
1-antichymotrypsin complexes were shown to induce the
IL-6 production in fibroblasts [94
]. On the other hand,
a number of proinflammatory cytokines play a fundamental role in the
induction of the lysosomal protease release from PMN [18
,
25
, 99
100
101
102
]. In particular, TNF-, IL-8,
and IL-6 are capable of inducing PMN degranulation (exocytosis), which
is accompanied by the release of NE, PR3, and Cat G into the
extracellular milieu.
Furthermore, cytokines are involved in the regulation of the production
and secretion of the major inhibitors of PMN-serine proteases, such as
the secretory leukocyte protease inhibitor, 1-proteinase
inhibitor and 1-antichymotrypsin
[103
104
105
106
]. Taken together, the increase of knowledge
over the last few years sheds new light on the physiological relevance
of extracellularly released PMN proteases. Nevertheless, the question
of the extent of their regulatory impact under various
pathophysiological conditions remains a matter of further
investigation.
|
ACKNOWLEDGEMENTS
|
|---|
We thank U. Lendeckel, D. Reinhold, E. Wrenger, T. Kaehne, and
K. H. Neumann for critical discussion of the manuscript.
Received June 2, 2000;
revised October 18, 2000;
accepted October 20, 2000.
|
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