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xß2 Integrin (CD11c-CD18, gp150-95)1
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Laboratoire de Biochimie Médicale et Biologie Moléculaire, Centre National de la Recherche Scientifique, UPRESA 6021, Institut Fedératif de Recherche 53-Biomolécules, Faculté de Médecine, Université de Reims Champagne-Ardenne, Reims, France; and
Laboratoire Central d’Hématologie, Centre Hospitalier Universitaire de Reims, rue du Général Koenig, Reims, France
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Abstract |
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xß2)
integrins, which promote their adhesion and activation. For monocyte
activation, specific domains of the type I collagen telopeptides are
necessary. Interactions between monocytes and collagen are most likely
involved in the cascade of events that characterize the initial phases
of inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that type I collagen, the most abundant
collagen in soft connective tissues, was able to bind and to activate
polymorphonuclear leukocytes (PMNs), as demonstrated by the emission of
pseudopods, secretion of lytic enzymes, and production of oxygen free
radicals (3, 4). This effect was shown to depend on
an integrin-linked pathway involving
Lß2 integrin (5, 6).
Other cell types are potentially involved in these phenomena through interactions with both ECM components and other cells present in the inflamed area. Human blood monocytes and their tissular counterpart macrophages, for instance, accumulate in the sites of inflammation and develop characteristic features of activation. In this process, the contacts between ECM molecules and monocytes not only ensure the binding of the cells, but also trigger intracellular events: for instance, the contact between monocytes and type I collagen enhances phagocytosis of opsonized bacteria (7) and secretion of IL-1 (8). However, the nature of the receptors involved in monocyte interactions with native type I collagen is still unclear.
In this study, we investigated the specific interactions between
monocytes obtained from human blood by elutriation and native type I
collagen. We report that binding of monocytes to type I collagen
significantly increases the production of superoxide anion
(O2-) and that this interaction
is mediated by the xß2
integrin (CD11c-CD18, gp150-95).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Culture medium RPMI 1640 and FCS were obtained from Life Technologies (Cergy Pontoise, France). Ferricytochrome c, superoxide dismutase, aprotinin, benzamidine, type V BSA, nitroblue tetrazolium (NBT), crystal violet, HEPES, leupeptin, n-octylglucoside, N-ethylmaleimide, PMSF, 5-bromo-4-chloro-3-indolyl phosphate (BICP/NBT; Sigma Fast), tetramethylene-diamine and alkaline phosphatase-coupled polyclonal Ab to mouse IgGs were purchased from Sigma (St. Louis, MO). Nonidet P-40, SDS, and acrylamide/bisacrylamide solutions were from BDH Laboratories (Poole, Dorset, U.K.). CNBr-Sepharose 4B was obtained from Pharmacia Biotech (Uppsala, Sweden). The following mAbs were used: P4C10, recognizing the ß1 integrin subunit (Life Technologies); MHM-23 and MHM-24, raised respectively against CD11a and CD18 (Dakopatts, Glostrup, Denmark); D-12 and 5-HCl-3, recognizing CD11b and CD11c; Leu-12, a specific anti-lymphocyte Ab (Becton Dickinson, Mountain View, CA); and MEM-25, Bear 1, FK-24, and MEM-48, recognizing CD11a, CD11b, CD11c, and CD18, respectively, from Monosan (Tebu, Paris, France). The synthetic peptides CGRGDSPC and DGGRYY were synthesized by Neosystem Laboratories (Strasbourg, France).
Polystyrene 96-well plates were bought from Nunc (Copenhagen, Denmark), and Treff polypropylene microtubes from Polylabo (Strasbourg, France).
Type I collagen was prepared in the laboratory from Sprague Dawley rat (Depre, St. Doulchard, France) tail tendons by 0.5 M acetic acid extraction (9) and used as native acid-soluble collagen or after pepsin digestion to remove telopeptides (10). Type I acid-soluble and pepsinized collagens used in this study were denatured by heating at 60°C for 30 min. We have verified that the preparations of type I collagen do not contain any contaminating fibrinogen (data not shown). All preparations were solubilized in 18 mM acetic acid at 250 µg/ml for experimental purpose. Human fibrinogen was a generous gift from Laboratoire Français du Fractionnement et des Biotechnologies (Les Ulis, France).
Cell incubations
Monocytes were prepared from total blood obtained from healthy volunteers after informed consent, and separated by elutriation (11). The purity of the preparations, assessed as the number of CD14-positive cells, was higher than 95%, and cell viability, assessed by trypan blue exclusion test, was higher than 98%. The cells were suspended in RPMI 1640 at a concentration of 1.5 x 106 cells/ml and used on the day of preparation.
Ninety-six-well plates were coated with acid-soluble collagen I, pepsin-digested collagen I, or BSA, 25 µg per well. Coated plates were washed three times with Dulbecco’s solution, and 100 µl of BSA 2% (w/v) was added in each well. Plates were incubated for 2 h at 37°C, and BSA was removed, then washed three more times with sterile Dulbecco’s solution before cell addition.
Measurement of cell adhesion
Cell adhesion was measured at 37°C using the method of cell nuclei staining by crystal violet (12). A total of 1.5 x 105 cells in 100 µl RPMI 1640 was added in each well and incubated from 0 to 4 h. In standard conditions, 1-h incubations were performed. After the incubation period, the nonadherent cells were discarded and the wells rinsed three times with 200 µl Dulbecco’s solution. The adherent cells were fixed with 100 µl of a 1.1% (v/v) glutaraldehyde solution for 15 min. After three washes with distilled water, 100 µl of crystal violet solution (0.1% (w/v) in 0.2 M HEPES buffer, pH 6) was added to each well, left for 20 min, and discarded. After extensive washing and drying of the plates, the coloration of the nuclei was extracted with 100 µl of a 1.8 M acetic acid solution, and the absorbance at 560 nm was evaluated spectrophotometrically. The number of adherent cells was calculated from a standard calibration curve obtained with an increasing number of cells fixed with 2.2% (v/v) glutaraldehyde solution.
Measurement of O2- production
O2- production by monocytes was measured using two procedures. In a first series of experiments, O2- production was measured simultaneously with monocyte adhesion, in 96-well plates. Monocytes were seeded in the conditions described above, NBT being added to the medium at the final concentration 1.67 x 10-5 M. After completion of the incubation (0–4 h), the supernatant was discarded and the intracellular reduction of NBT was measured spectrophotometrically at 560 nm (13). In another series of experiments, O2- production was measured by the superoxide dismutase-inhibitable reduction of ferricytochrome c (14), using monocyte suspension in test tubes, as previously described (3). Briefly, 1.5 x 106 monocytes were suspended in 850 µl of Dulbecco’s solution supplemented with 100 µl of 1 mM ferricytochrome c solution. O2- production was evaluated after addition of 100 µl of a 2 mg/ml solution of collagen I in 18 mM acetic acid. The increase of absorbance at 550 nm was evaluated spectrophotometrically, test tubes supplemented with 50 µl of a 1000 U/ml superoxide dismutase solution being used as blanks to assess the specificity of the reaction.
Effect of divalent cations and EDTA on monocytes
The effect of divalent cations and EDTA, a chelator of divalent cations, on monocyte adhesion and O2- production, was studied. Monocytes were preincubated for 10 min at 37°C under gentle stirring in Dulbecco’s solution with different concentrations of Ca2+, Mg2+, and/or Mn2+, or with 5 mM EDTA, then dispensed in 96-well plates and treated as above, cations and EDTA being maintained in the incubation medium throughout the experiment.
Effect of anti-integrin mAbs on monocytes
The effect of mAbs raised against various integrin subunits on monocyte adhesion and activation was studied according to the following protocol: polypropylene microtubes were coated with 1 ml FCS under agitation at 37°C for 1 h and extensively washed with a 0.15 M NaCl solution. A total of 100 µl of the Ab solution at the appropriate titer (6 µg IgG/ml) was added to 1.5 x 106 monocytes in 900 µl Dulbecco’s solution containing 1.3 mM CaCl2 and 1 mM MgCl2. Microtubes were shaken horizontally at 150 cycles/min for 90 min at 37°C (5, 15). Monocyte adhesion and O2- production on collagen I were then evaluated as described above, in the continuous presence of mAbs in the incubation medium.
Affinity chromatography
Eight micrograms of purified, heat-denatured, acid-soluble, or pepsin-digested type I collagen, or human fibrinogen were covalently coupled to 1.5 g of CNBr-activated Sepharose 4B, according to the instructions of the manufacturer. Meanwhile, a suspension of 2 x 108 monocytes in a 20 mM Tris-HCl buffer, pH 7.5, containing 2 mM EDTA, 2 mM PMSF, 2 mg/ml leupeptin, and 0.25 M sucrose, was sonicated, then centrifuged at 100,000 x g for 1 h at 4°C. After removal of the supernatant, cell preparations were extracted in a 100 mM Tris-HCl buffer, pH 8.1, containing 0.15 M NaCl, 2 mM PMSF, 1% (w/v) aprotinin, 0.5% (w/v) Nonidet P-40, and 0.1% (w/v) SDS, sonicated, and maintained under agitation for 2 h at 4°C. The membrane extract was then diluted to 1/5 (v/v) with a 10 mM Tris-HCl buffer, pH 7.4, containing 1.3 mM CaCl2, 1 mM MgCl2, 1 mM benzamidine, 2 mM PMSF, and 0.1% (w/v) octylglucoside, to decrease the concentration of Nonidet P-40 and SDS for the binding step. This extract was transferred onto the collagen or fibrinogen-Sepharose 4B beads in batch, and incubated overnight at 4°C, under gentle horizontal agitation.
The suspension was packed into a 1-cm-diameter glass column, and washed with buffer A (10 mM Tris-HCl buffer, pH 7.4, containing 1.3 mM CaCl2, 1 mM MgCl2, 1 mM benzamidine, 2 mM PMSF, and 0.1% (w/v) octylglucoside) at a flow of 0.24 ml/h. The bound materials were then eluted using successively three different buffers: buffer B (10 mM Tris-HCl buffer, pH 7.4, containing 5 mM EDTA, 0.15 M NaCl, 1 mM benzamidine, 2 mM PMSF, 0.1% (w/v) octylglucoside), buffer C (same as buffer B, but with 1 M NaCl), and buffer D (3 M guanidinium chloride).
Fractions of 1 ml were collected, and their absorbance was measured at 280 nm. Proteins contained in the elution peaks were precipitated by 80% (v/v) ethanol overnight at -20°C, and precipitates were redissolved in a Laemmli sample buffer before electrophoresis (16).
Western blotting procedures
Aliquots of the eluted fractions corresponding to 50 µg proteins as evaluated by A280 measurement were submitted to electrophoresis in a 7.5% polyacrylamide gel under reducing conditions (SDS-PAGE). Total proteins were stained using Coomassie brilliant blue R-250 (CBB R-250). Immunological characterization of eluted proteins was done as follows (17). Proteins separated by SDS-PAGE were blotted on a transfer Immobilon membrane (Millipore, Bedford, MA), which was saturated by incubation in a TBS-Tween buffer (20 mM Tris-HCl buffer, pH 7.2, with 0.15 M NaCl, and 0.5% (w/v) Tween-20) containing 2% (w/v) BSA, for 1 h at room temperature. After extensive rinsing with TBS-Tween buffer, the membrane was incubated in TBS buffer containing the appropriate mAb (5 µg IgG/ml) overnight at 4°C. The final revelation was achieved by incubation with an alkaline phosphatase-coupled anti-IgG Ab for 1 h at 4°C and addition of Sigma Fast reagent (1 tablet for 10 ml TBS). Staining was stopped by rinsing on distilled water after revelation of the bands, and the membrane was dried on absorbant paper. The migration of the bands was compared with that of molecular mass markers stained by CBB R-250.
Statistics
All results were expressed as mean ± SEM. Statistical significance of the differences was studied using the Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When monocytes were distributed in BSA-coated wells, adhesion
occurred at 30 min and increased until reaching a plateau at 3 h.
A faster adhesion was noticed when wells were coated with acid-soluble
or pepsin-digested type I collagen, being almost complete after 1 and
2 h, respectively (Fig. 1
A).
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B). When collagen-induced
O2- production was
measured in test tube by the superoxide dismutase-inhibitable
reduction of ferricytochrome c, similar results were
obtained (Fig. 1C). In the next experiments, the incubation time was maintained constant at 1 h, owing to the results of the kinetic experiments.
Synthetic peptides CGRGDSPC and DGGRYY, which have been demonstrated in competition experiments to be responsible for O2- production by PMNs triggered by type I collagen (4), had no effect on monocyte adhesion and production of O2- induced by collagen I (data not shown).
Effect of type I collagen denaturation on monocyte adhesion and superoxide production
Acid-soluble and pepsin-digested type I collagens were denatured
by heating at 60°C during 30 min. Adhesion of monocytes on either
native or denatured acid-soluble collagen I showed no significant
difference. The same results were obtained for pepsin-digested collagen
I (Fig. 2A).
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B). Effect of divalent cations and EDTA on monocyte adhesion and superoxide production induced by type I collagen
Monocyte adhesion and O2-
production triggered by acid-soluble type I collagen were studied in
the presence of different concentrations of divalent cations or 5 mM
EDTA. Monocyte adhesion to collagen I was maximal with 1.3 mM
Ca2+ and 1 mM Mg2+ (Fig. 3A). The presence of
Ca2+ and Mg2+ was necessary
for monocyte activation (Fig. 3B). The addition of EDTA in
the preincubation and in the incubation medium significantly inhibited
the adhesion of monocytes to collagen I. Adhesion was decreased by 85%
(p < 0.001) in the presence of 5 mM EDTA (Fig. 3A). The same was noticed regarding
O2- production, which was
inhibited by 81% (p < 0.001) at the same
concentration of EDTA (Fig. 3B). When 1 mM
Mn2+ was added in the optimal conditions
described above (1.3 mM Ca2+ and 1 mM
Mg2+), adhesion to acid-soluble type I collagen
was increased (+82%, p < 0.001), whereas
O2- production was inhibited by
98% (p < 0.001) (data not shown).
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Effects of mAbs on monocyte adhesion to acid-soluble type I collagen
mAbs raised against several integrin subunits were preincubated
with monocytes and maintained in the medium after seeding in 96-well
collagen I-coated plates. Their effect on monocyte adhesion was checked
after 1-h incubation. Controls were realized by preincubating monocytes
1) in Dulbecco’s solution containing 1.3 mM
CaCl2 and 1 mM MgCl2, and
2) in the same solution containing the anti-lymphocyte Ab clone
Leu-12. Two Abs against CD11c subunit (clones FK-24 and 5-HCl-3)
significantly inhibited the adhesion of monocytes to type I collagen,
by 86% and 45%, respectively (p < 0.001).
Two Abs raised against CD18 subunit (clones MEM-48 and MHM-23) also
inhibited monocyte adhesion, by 81% and 72%, respectively
(p < 0.001). Abs raised against CD11a and
CD11b subunits had no significant inhibitory effect, nor had the
anti-lymphocyte Ab (clone Leu-12), used as control. The
anti-CD29 (ß1 subunit) mAb used, clone
P4C10, slightly (-16%) but significantly (p
< 0.001) inhibited monocyte adhesion to acid-soluble type I collagen
(Fig. 4A). Similar results
were obtained with pepsin-digested collagen I (data not shown). No
significant inhibition of monocyte adhesion to BSA was induced by these
antisera (data not shown).
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The effect of mAbs directed against several integrin subunits on
O2- production by monocytes was
checked using the superoxide dismutase-inhibitable reduction of
ferricytochrome c reaction. When monocytes were incubated
with anti-CD11a, anti-CD11b, or anti-lymphocyte (used as
additional control) Abs, which are blocking Abs (6), no
inhibition of collagen I-induced
O2- production was noticed. In
the same way, the mAb anti-CD29 (ß1
subunit) had no effect. On the contrary, both Abs directed against
CD11c (clones FK-24 and 5-HCl-3) and CD18 (clones MEM-48 and MHM-23)
strongly inhibited (p < 0.001)
O2- production: -91% and
-62%, and -87% and -70%, respectively (Fig. 4B).
Identification of the receptor mediating monocyte type I collagen interactions
The nature of the receptor involved in monocyte type I collagen
interactions was studied in the case of both acid-soluble and
pepsin-digested type I collagen, as monocyte adhesion on both forms of
collagen was inhibited in a similar way by anti-integrin mAbs. For
investigating interaction specificity, we included chromatography on a
known xß2 ligand,
fibrinogen, and a nonspecific negative control, CNBr-activated
Sepharose 4B saturated by 0.1 M Tris-HCl, pH 8.1 (no fixation of
monocyte membrane extracts occurred on this support; data not shown).
The affinity chromatography of monocyte membrane extracts on
acid-soluble and pepsin-digested type I collagens and fibrinogen
coupled with Sepharose-4B displayed comparable elution profiles (Figs. 5A,
6A, and
7A). Fractions eluted by
affinity chromatography on acid-soluble and pepsin-digested collagens
with buffer B containing 5 mM EDTA and 0.15 M NaCl showed a major
band of molecular mass 95 kDa and a minor band of molecular mass
150 kDa, whereas elution with 1 M NaCl or 3 M guanidinium chloride did
not elute additional material (Figs. 5B and 6B).
In the case of fibrinogen, a major additional band of molecular mass
180 kDa was obtained (Fig. 7B), as previously described
(18, 19). The analysis of the bound materials in minor
peaks 3 and 4 showed no elution of additional materials, except low
amounts of materials migrating at the front (data not shown).
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). In both cases, Western
blotting using anti-CD11c Ab (clone FK-24) showed a major band of
molecular mass 150 kDa (Fig. 8A). The anti-CD18 Ab
(clone MEM-48) revealed a major band of 95 kDa (Fig. 8B). By
contrast, no reaction was noticed between bands obtained from collagen
affinity chromatography and CD11b Ab (Fig. 8C). Western
blotting using anti-CD11b Ab (clone D-12) showed a major band of
molecular mass 180 kDa after affinity chromatography with
fibrinogen-Sepharose (Fig. 8C). These results show that
monocytes bind to both acid-soluble and pepsin-digested type I collagen
through a CD11c-CD18 integrin.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous works of our laboratory have shown that type I collagen was able to deeply influence the metabolism of cells involved in these processes, in the case of fibroblasts (22, 23) as well as PMNs (3, 4, 5, 6). In this work, we present new evidences that type I collagen interactions with monocytes are critical events involved in these processes. Cell preparations we used were purified human monocytes, devoid of any lymphocyte contamination, instead of continuous cell lines of monocyte-like cells, as used in many other studies. Moreover, Dransfield et al. (24) have shown that the technique of isolation of monocytes by elutriation did not modify the number of CD11c receptors available on plasma membrane for adhesion.
As we have previously shown with PMNs, we report in this work that acid-soluble collagen I induced a significant cell activation characterized by O2- production. However, we noticed that pepsin-digested collagen I induced a slight production of O2- by monocytes, which is a difference with PMNs. This suggests that collagen I activates monocytes or PMNs through distinct transduction pathways. This hypothesis is supported by the fact that the synthetic peptides CGRGDSPC and DGGRYY, which were shown to be responsible for collagen I-induced activation in PMNs, did not influence monocyte activation, thus suggesting the involvement of different receptors for type I collagen in PMNs and monocytes. It should also be noticed that oxygen free radicals production by collagen-activated monocytes does not require the presence of serum (data not shown), contrasting with the stimulation by LPS (25).
Another important point is the respective role of primary structure and fibrillar organization of collagen on its interactions with monocytes. For instance, under static conditions, it was shown that platelet adhesion to type I fibrillar and monomeric collagen was similar (26). In the presence of Mg2+, platelet adhesion to fibrillar collagen induced activation of gpIIb-IIIa complex and complete spreading, whereas platelet adhesion to monomeric collagen resulted only in partial activation of gpIIb-IIIa complex and spreading. In the case of monocytes, adhesion to either native or denatured acid-soluble collagen I showed no significant difference, suggesting the major role of the primary structure compared with the fibrillar organization of the molecule.
The involvement of at least one integrin in monocyte-collagen
interactions was suggested by the experiments using divalent
cations and EDTA inhibition. Previous studies of others have shown
the biological relevance of this interaction. The contact between
monocytes and type I collagen was shown to induce the release of
TNF-, IL-6, and O2-
(27). In the mentioned study, however, the form of
collagen I used (acid soluble or pepsin digested) was not precised. On
the other hand, monocyte adhesion to collagen increased bacterial
phagocytosis by activation of CR1, CR3, and Fc receptors
(7).
We characterized the integrin involved in monocyte-collagen I
interactions by the use of immunological methods. Our results indicate
the involvement of xß2
integrin (CD11c-CD18) in this process. Various studies showed that
CD11c-CD18 integrins are concentrated in adhesion sites, mainly in
podosomes, together with other submembranous components such as
vinculin or talin, in focal adhesions (28). As well,
CD11c-CD18 integrins were shown to regulate monocyte adhesion and
diapedesis (29). It should be noticed that integrin
expression is modulated during monocyte differentiation into
macrophages, with an increased expression of CD11c (30).
In this regard, the role of collagen on monocyte differentiation
through xß2
interaction might be important, as suggested by a previous study on
dendritic cells (31).
Other studies bring arguments for the involvement of
ß1 integrins as monocyte receptors for
collagen. Experiments of others dealing with monocyte adhesion on
collagen, but no data concerning
O2- production, suggested the
role of 5ß1 integrins
(32). In their study, however, the characteristics of the
Ab used were not well defined, and denatured collagen was used as
adhesion substratum. Moreover, these experiments were done with a
monocyte-enriched preparation obtained from Ficoll gradient instead of
pure monocytes obtained by elutriation. In another study, the mAb to
ß1 integrin (clone P4C10) was shown to inhibit
monocyte-like cell adhesion to fibronectin (33), but the
concentration used was 10-fold higher than that we used. Moreover,
receptors involved in the interactions with fibronectin may be very
different from that involved in the case of collagen. In this latter
case again, the type of cells used (THP-1) was different from ours, and
other authors have shown that THP-1 cells might differentially interact
with collagen (34). We have found that
anti-ß1 mAb induced a slight but
significant inhibition of monocyte adhesion, but was ineffective on
monocyte activation by collagen. ß1 integrins
may play a true role, although less important than
ß2 integrins, in collagen-monocyte interaction,
suggesting that other integrins, or integrin-associated proteins, may
also mediate monocyte adhesion onto collagen.
Taken together, our results indicate that
xß2 integrin
(CD11c-CD18, gp150–95) is a major membrane receptor involved in the
interactions between monocytes and type I collagen, eliciting
transduction pathways leading to monocyte activation, that should be
further investigated. This type of cell-matrix interaction is likely to
participate in the complex network of reactions that involve monocytes,
other inflammatory cells, and fibroblasts in inflammation or wound
healing through reactive oxygen species and cytokine production
(8). For instance, IL-1, a major product of monocyte, is
known as a potent modulator of fibroblast functions (35),
which are of major importance in these processes. The precise knowledge
of these various interactions should allow a better monitoring of these
pathophysiological events, with new therapeutic perspectives.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Philippe Gillery, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Centre National de la Recherche Scientifique, UPRESA 6021, Faculté de Médecine, Université de Reims Champagne-Ardenne, 51095 Reims Cedex, France.
3 Abbreviations used in this paper: ECM, extracellular matrix; CBB, Coomassie brilliant blue; NBT, nitroblue tetrazolium; O2-, superoxide anion; PMN, polymorphonuclear leukocyte.
Received for publication August 23, 1999. Accepted for publication March 15, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 (III) chain of human collagen. Biochemistry 13:3459.[Medline]
1ß1 and 2ß1 integrins. J. Cell Biol. 131:1903.2ß1 integrin and GP VI. J. Biol. Chem. 274:11897., IL-6, and superoxide production. J. Leukocyte Biol. 57:63.[Abstract]
5ß1 integrin activates the 2ß1 receptor via the 5 subunit cytoplasmic domain and protein kinase C. J. Immunol. 153:2222.[Abstract]
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) or pepsin-digested (
) type I
collagen, or BSA used as control (•) (A and
B), or incubated in test tubes with the same components
(C). The results of cell adhesion measured by the
crystal violet method (A), O2-
production measured by NBT reduction (B), and
O2- production measured by superoxide
dismutase-inhibitable reduction of ferricytochrome c
(C), respectively, are shown. Results are the means of
12 experiments ± 1 SEM.
